Global Compliance Perspective on HMOs: Approvals and Applications in the US

Human Milk Oligosaccharides (HMOs) are unique components found exclusively in human breast milk. They are the third most abundant solid component in human milk and exhibit a variety of biological functions, including modulation of gut microbiota and support of cognitive development.

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There are more than 200 types of HMOs, each with specific structures and functions, enabling applications across different fields. As a result, regulatory submissions for HMOs are rapidly increasing worldwide, with commercialization first initiated in Europe and the United States.

In 2015, the U.S. Food and Drug Administration (FDA) recognized the first HMO – chemically synthesized 2’-fucosyllactose (2’-FL) submitted by Glycom A/S – as Generally Recognized as Safe (GRAS).

Since then, multiple HMOs have successively obtained GRAS status in the United States. Details are summarized below.

Table 1. GRAS-Approved HMOs in the United States

No.	Substance	First Approval Date	Number of GRAS Notices
1	2’-FL	2015.09.16	14
2	3-FL	2021.02.08	4
3	3’-SL	2018.09.26	6
4	6’-SL	2020.02.24	5
5	LNT	2019.10.07	4
6	LNnT	2015.10.02	6
7	2’-FL/DFL	2019.08.20	1
8	LNFP-Ι/2’-FL	2023.01.19	1

2’-FL

As the earliest approved HMO in the U.S., a total of 14 GRAS notices had been submitted for 2’-FL as of December 31, 2025.

The first GRAS notification (GRN No. 571, 2015) covered microbial-derived 2’-FL with intended use limited to infant formula, at a maximum level of 2 g/L.

Subsequently, the intended uses expanded to a wide range of conventional foods. Among them, GRN No. 1051 includes the broadest application scope and higher use levels. Later approvals (GRN No. 1157 and 1238) follow similar conditions. Table 2 summarizes intended uses and maximum levels.

Table 2. Intended Uses/Maximum Use Levels of 2’-FL (GRN No. 1051)

Intended Uses	Maximum Use Levels (g/kg or g/L)
Gluten-free bread and bakery products	48
Carbonated beverages	1.2
Fortified water	1.2
Sports drinks, isotonic drinks, and energy drinks	6
Ready-to-eat hot breakfast cereals	31
Puffed ready-to-eat cereals	80
High-fiber ready-to-eat cereals	40
Biscuit-type ready-to-eat cereals	40
Coffee and tea	10
Dairy alternatives	1.2
Beverage whiteners (powder)	600
Beverage whiteners (liquid)	80
Non-dairy yogurt	12
Frozen dairy desserts	17
Puddings, custards, and panna cotta	17
Fruit pie fillings	14.1
Fruit fillings for bars, cookies, yogurt, and cakes	30
Non-exempt infant formula for term infants	2.4
Young child formula (>12 months)	2.4
Hot cereals for infants and young children, dry form, ready-to-eat	12
Other foods for infants and young children: yogurt, fruits, vegetables, toddler meals, desserts	12
Other beverages for infants and young children: fruit juice, yogurt drinks	10
Infant snacks: wafers, crackers, cookies, other dried snacks	57
Jams, jellies, preserved fruits, fruit pastes	60
General meal replacement bars	30
Cereal bars, including snack bars, granola bars, and breakfast bars	30
Meal replacement bars for weight management	40
General meal replacement beverages (including nutritional drinks and smoothies), dairy-based or non-dairy	5
Meal replacement beverages for weight management, dairy-based or non-dairy	12
Dairy-based meal replacement beverages for children (e.g., children's nutritional drinks)	12
Plain pasteurized milk and UHT milk	1.2
Skimmed milk	1.2
Flavored fermented milk	1.2
Yogurt	12
Fruit juice and fruit purée beverages	1.2
Fruit-flavored drinks and juice drinks	1.2
Vegetable juice and purée beverages	1.2
Sugar substitutes: table-top sweeteners	300
Syrups for flavoring milk beverages	7
Nutritional beverages for pregnant women	12
Oral and enteral tube feeding formula foods (>11 years)	20

Note: Items highlighted in red in the table indicate uses in infant formula products; the same applies below

3-FL

As of December 31, 2025, a total of four 3-FL products have received FDA GRAS notifications, namely GRN No. 925, GRN No. 951, GRN No. 1037, and GRN No. 1099. With ongoing submissions, the intended uses of 3-FL have expanded from infant formula to multiple categories of general foods, as detailed in Table 3 below.

Table 3. Intended Uses/Maximum Use Levels of GRAS Notified 3-FL Products

GRN No./Date	Intended Uses and Maximum Use Levels
GRN No. 925 /2021.02.08	Intended as an ingredient in non-exempt infant formula for term infants (cow’s milk–based) at a use level of 0.44 g/L (as consumed).
GRN No. 951 /2021.08.12	Intended as an ingredient in non-exempt formula for term infants and toddlers aged 1–3 years (cow’s milk– or soy-based) at 0.44 g/L (as consumed); in juices, beverages, and foods for infants and children under 3 years, at 0.44–4.4 g/kg; in cereal bars, nutrition bars, fortified waters, energy drinks and sports drinks, breakfast cereals, dairy alternatives, yogurt, fermented milk, flavored milk, smoothies, dairy-based meal replacement beverages, fruit and purée beverages, vegetable juice, and oral/enteral tube feeding formula foods, the maximum use levels range from 0.26 to 8.8 g/kg.
GRN No. 1037 /2022.11.07	Intended as an ingredient in non-exempt infant formula for term infants at 0.75 g/L (as consumed); in formula and beverages for children over 12 months, at 0.90 g/L (as consumed); in foods for infants and young children, at 6.25 g/kg; in meal replacement nutritional beverages, sports drinks, isotonic drinks, soft drinks, energy drinks, fortified waters, meal replacement bars, nutrition bars, cereal bars, flavored and unflavored milk, skim milk, yogurt, yogurt drinks, probiotic beverages, and fruit beverages, the maximum use levels range from 1.25 to 25 g/kg.
GRN No. 1099 /2023.08.29	Intended as an ingredient in non-exempt infant formula for term infants (cow’s milk–, soy–, and partially hydrolyzed protein–based) at ≤0.9 g/L (as consumed); in formula for toddlers aged 1–3 years, at ≤1.2 g/L (as consumed); in other beverages and foods for infants and children under 3 years (including yogurt and juice), at ≤0.44 g/kg; in hot cereals, thin crackers, crispbreads, cookies, and snacks, at ≤4.4 g/kg; in cereal bars, granola bars, energy bars, protein bars, and meal replacement bars, fortified waters, sports drinks, isotonic drinks, energy drinks, breakfast cereals, fermented milk, flavored milk, smoothies, yogurt, meal replacement beverages (dairy-based and non-dairy), dairy alternatives, fruit and purée beverages, flavored juice drinks, and chewing gum, the maximum use levels range from 0.26 to 8.8 g/kg; in oral and enteral tube feeding formula foods (≥11 years), at 6.6 g/L (as consumed).

3’-SL

As of December 31, 2025, a total of six 3’-SL products have received FDA GRAS recognition, namely GRN No. 766, GRN No. 880, GRN No. 921, GRN No. 1015, GRN No. 1052, and GRN No. 1074. The intended uses and maximum use levels are shown in Table 4 below. Among them, GRN No. 1015 has no uses related to infant formula.

Table 4. Intended Uses / Maximum Use Levels of GRAS Notified 3’-SL Products

GRN No./Date	Intended Uses and Maximum Use Levels
GRN No. 766 /2018.09.26	Intended as an ingredient in non-exempt formula for term infants, with a maximum use level of 238 mg/L (as consumed); when used in dairy analogs, foods for infants and young children, milk (whole and skim), dairy products, cereal products, beverages and beverage bases, and sugar substitutes, the content ranges from 24–3000 mg/RACC.
GRN No. 880 /2020.04.13	Intended as an ingredient in cow’s milk–based non-exempt formula for term infants at up to 0.2 g/L; in formula and beverages for toddlers (>12 months), at 0.15 g/L; in foods for infants and young children, at 1.25 g/L; in yogurt, at 2.5 g/kg; in skim milk and liquid milk (flavored and unflavored), at 0.25 g/L; in meal replacement beverages, at 0.5 g/L; in meal replacement bars, at 5 g/kg; in cereal and granola bars, at 2.5 g/kg; in soft drinks, fruit drinks, sports drinks, energy drinks, and fortified waters, at 0.25 g/L.
GRN No. 921 /2020.10.30	Intended as an ingredient in dairy-based non-exempt infant formula at 0.28 g/L (as consumed).
GRN No. 1015 /2022.07.15	Intended as an ingredient in toddler formula (>12 months) at 0.28 g/L (as pure substance); in dairy- and soy-based children’s and adult meal replacement beverages, at 0.9 g/L; in ready-to-eat cereals, snack bars, breakfast bars, and meal replacement bars for children under 3 years, at 1.0 g/kg; in non-carbonated sports drinks and flavored waters, at 0.45 g/L; in enteral feeding formula foods, at 1.5 g/L.
GRN No. 1052 /2023.04.18	Intended as an ingredient in non-exempt formula for term infants and toddler formula (>12 months), at 0.24 g/L (as consumed); in infant and young child beverages, at 0.15–1.0 g/L; in infant hot cereals, desserts, dried snacks, and other foods, at 1.1–5.7 g/kg; in non-alcoholic beverages (sports and functional drinks, fortified and flavored waters, soft drinks, coffee and tea, fruit juice and purée drinks, fruit-flavored drinks, vegetable juice and vegetable purée, milk, flavored milk, skim milk, dairy alternatives, meal replacement and protein beverages), at 0.12–6.0 g/L; in oral nutritional supplements and enteral tube feeding formula foods (≥11 years), at 2.0 g/L; in chewing gum and table-top sweeteners, at 30 g/kg; in beverage whiteners and cream substitutes, at 60 g/kg; in bread and bakery products, breakfast cereals, frozen dairy desserts, fruit ice, gel puddings and fillings, cereal bars and granola bars (including meal replacement bars), jams and jellies, yogurt (including non-dairy yogurt), condensed milk, canned fruit, fruit-based desserts, and syrups, at 0.12–8.0 g/kg.
GRN No. 1074 /2023.04.05	Intended as an ingredient in non-exempt formula for term infants, with a maximum use level of 0.28 g/L (as consumed); for other food categories, maximum limits are established.

6’-SL

As of December 31, 2025, a total of five 6’-SL products have received FDA GRAS recognition, namely GRN No. 881, GRN No. 922, GRN No. 1016, GRN No. 1053, and GRN No. 1075. The intended uses and maximum use levels are shown in Table 5 below. Among them, GRN No. 1053 has the broadest intended uses.

Table 5. Intended Uses / Maximum Use Levels of GRAS Notified 6’-SL Products

GRN No./Date	Intended Uses and Maximum Use Levels
GRN No. 881 /2020.02.24	Intended as an ingredient in non-exempt cow’s milk–based infant formula for term infants, at 0.4 g/L (as consumed); in toddler formula (>12 months) and beverages, at 0.3 g/L (as consumed); in foods for infants and young children, at 2.5 g/kg; in yogurt, at 5 g/kg; in skim milk and liquid milk (flavored and unflavored), at 0.5 g/L; in meal replacement beverages, at 1 g/L; in meal replacement bars, at 10 g/kg; in cereal and granola bars, at 5 g/kg; in soft drinks, fruit drinks, sports drinks, energy drinks, and fortified waters, at 0.5 g/L.
GRN No. 922 /2021.04.23	Intended as an ingredient in non-exempt cow’s milk–based infant formula for term infants, at 0.4 g/L (as consumed).
GRN No. 1016 /2022.07.15	Intended as an ingredient in toddler formula (>12 months), at 0.4 g/L (as consumed); in dairy-based children’s and adult meal replacement beverages, at 2.28 g/L; in ready-to-eat cereals, snack bars, breakfast bars, and meal replacement bars for children under 3 years, at 1.5 g/kg; in non-carbonated sports drinks and flavored waters, at 0.7 g/L; in enteral tube feeding formula foods, at 3.8 g/L.
GRN No. 1053 /2023.05.12	Intended as an ingredient in non-exempt infant formula for term infants, at 0.4 g/L (as consumed); in toddler formula (1–3 years), at 0.5 g/L (as consumed); in infant and young child beverages, at 2.1 g/L; in hot cereals, desserts, dried snacks, and other foods for infants and young children, at 2.3–12 g/kg; in non-alcoholic beverages (sports drinks, energy drinks, flavored drinks, soft drinks, coffee and tea, fruit juices and fruit drinks, meal replacement and protein beverages), at 0.25–12.5 g/L; in oral and enteral tube feeding formula foods, at 4.1 g/L; in chewing gum and sugar substitutes, at 62 g/kg; in beverage whiteners and cream substitutes, at 125 g/kg; in baked goods and pre-mixes, breakfast cereals, frozen dairy desserts, fruit ice, gel-based desserts, puddings, fillings, cereal and granola bars (including meal replacement bars), jams and jellies, yogurt (including non-dairy yogurt), canned fruits, fruit-based desserts, and syrups, at 1.0–17.0 g/kg.
GRN No. 1075 /2023.03.22	Same as GRN No. 881.

LNT

As of December 31, 2025, a total of four 5-LNT products have received FDA GRAS recognition, namely GRN No. 833, GRN No. 923, GRN No. 1017, and GRN No. 1068. The intended uses and maximum use levels are shown in Table 6 below.

Table 6. Intended Uses / Maximum Use Levels of GRAS Notified LNT Products

GRN No./Date	Intended Uses and Maximum Use Levels
GRN No. 833 /2019.10.07	Intended as an ingredient in non-exempt cow’s milk–based infant formula for term infants, with a maximum use level of 0.8 g/L; in toddler beverages (including toddler formula), at 0.6 g/L; in foods for infants and young children (including toddler foods), at 5 g/kg; in yogurt, at 10 g/kg; in liquid milk (flavored and unflavored), at 1 g/L; in meal replacement beverages, at 2 g/L; in meal replacement bars, at 20 g/kg; in cereal and oat bars, at 10 g/kg; in soft drinks, fruit-based beverages, sports drinks, energy drinks, and fortified waters, at 1 g/L.
GRN No. 923 /2021.02.02	Intended as an ingredient in non-exempt cow’s milk–based infant formula for term infants, with a maximum use level of 0.8 g/L.
GRN No. 1017 /2022.08.23	Intended as an ingredient in toddler formula and electrolyte solutions, at 0.6 g/L; in children’s dairy-based meal replacement beverages, ready-to-eat instant cereal foods for infants and young children, meal replacement beverages, meal replacement bars, snack bars, and breakfast bars, at 6 g/L; in non-carbonated beverages, at 3 g/L; in enteral tube feeding formula foods, at 10 g/L.
GRN No. 1068 /2023.06.05	Intended as an ingredient in non-exempt infant formula for term infants, with a maximum use level of 0.8 g/L; in toddler formula and other beverages, up to 0.6 g/L; in foods for infants and young children, up to 5.0 g/kg; in sports drinks, isotonic drinks, energy drinks, soft drinks, fortified waters, fruit drinks, liquid milk (flavored and unflavored), and skim milk, up to 1.0 g/L; in meal replacement bars, up to 20 g/kg; in cereal and granola products, at 10 g/kg; in yogurt, up to 10 g/kg.

LNnT

As of December 31, 2025, a total of six LNnT products have received FDA GRAS recognition, namely GRN No. 547, GRN No. 659, GRN No. 895, GRN No. 919, GRN No. 1059, and GRN No. 1067. The intended uses and maximum use levels are shown in Table 7 below. Except for GRN No. 1059, the other five LNnT products have similar intended uses, with significant differences in maximum use levels in general foods, primarily reflecting higher usage levels. GRN No. 1059 has a distinct intended use, being applicable to exempt infant formula.

Table 7. Intended Uses / Maximum Use Levels of GRAS Notified LNnT Products

GRN No./Date	Intended Uses and Maximum Use Levels
GRN No. 547 /2015.10.02	Intended for use in infant formula for term infants, with a maximum use level of 600 mg/L; in baked goods and baking mixes, beverages and beverage bases, coffee and tea, dairy alternatives, foods for infants and young children, cereal products and pasta, milk (whole and skim), processed fruits and juices, processed vegetables and vegetable juices, and sugar substitutes, at 0.02–1.2 g per serving.
GRN No. 659 /2016.11.23	Intended for use in non-exempt cow’s milk–based infant formula for term infants, with a maximum use level of 600 mg/L; in beverages and beverage bases, dairy alternatives, milk (whole and skim), dairy products, processed fruits and juices, cereal products and pasta, and foods for infants and toddlers (including follow-on formula), at 0.2–3 g per serving.
GRN No. 895 /2020.12.03	Intended for use in beverages and beverage bases, dairy alternatives, foods for infants and young children (including term infant formula), cereal products and pasta, whole and skim milk, dairy products, and processed fruits and juices, at 0.02–0.68 g per serving.
GRN No. 919 /2020.10.30	Intended for use in non-exempt formula for term infants, toddler formula, and other toddler beverages, with a maximum use level of 0.6 g/L; in beverages and beverage bases, dairy alternatives, milk (whole and skim), and processed fruits and juices, up to 2.5 g/L; in cereal products, pasta, and foods for infants and young children, up to 20 g/kg.
GRN No. 1059 */2022.12.02*	Intended as an ingredient in exempt infant formula, suitable for term infants with milk protein allergy, multiple food allergies, non-allergic gastrointestinal disorders, or malabsorption, with a maximum use level of 600 mg/L (as consumed).
GRN No. 1067 /2023.04.04	Intended for use in non-exempt formula for term infants, with a maximum use level of 0.6 g/L; in toddler formula (>12 months), up to 0.6 g/L; in toddler beverages, up to 0.58 g/L; in foods for infants and young children, up to 3.0 g/L; in sports drinks, isotonic drinks, energy drinks, milk (flavored and unflavored), milk substitutes, skim milk, and fruit juices and purées, up to 0.58 g/L; in yogurt (including non-dairy yogurt), up to 2.67 g/kg; in meal replacement beverages, up to 2.5 g/L; in meal replacement bars, up to 20 g/kg.

2’-FL/DFL

2’-FL/DFL was recognized as GRAS by the FDA on August 20, 2020. The intended uses and use levels are as follows:

As an ingredient in non-exempt infant formula for term infants, with a maximum use level of 1.6 g/L; In toddler formula and other toddler beverages (1–3 years), at 1.2 g/L; In other foods for infants and young children, at 10 g/kg; In conventional foods, beverages and beverage bases, cereal products, pasta, milk (whole and skim), and dairy products intended for the general population, at 2–40 g/kg.

LNFP-I/2’-FL

LNFP-I/2’-FL was recognized as GRAS by the FDA on January 19, 2023. The use levels follow the maximum use levels of LNFP-I, with specific ranges shown in Table 8.

Table 8. Intended Uses / Maximum Use Levels of GRAS Notified LNFP-I/2’-FL Products

Intended Uses	Maximum Use Levels of LNFP-Ι (g/kg or g/L)
Non-exempt infant formula for term infants	0.8
Toddler formula	0.8
Other foods for infants and young children	8.33
Other beverages for infants and young children	1.2
Non-dairy meals and nutritional beverages	2.0
Sports drinks, isotonic drinks, energy drinks, soft drinks, and fortified waters	1.0
Meal replacement bars for weight management	20
Cereal and nutrition bars	20
Unflavored pasteurized and sterilized milk	1.0
Skim milk	1.5
Flavored milk	1.5
Dairy-based meal replacement and nutrition beverages	2.0
Fermented milk-based beverages	1.5
Yogurt	10.0
Fruit-flavored beverages and fruit juice drinks	1.0

It can be observed that multiple HMOs have already received GRAS notification in the United States. The intended uses of HMOs now include both infant and young child formula as well as a variety of conventional foods, with use levels higher than those in the initial submissions. When submitting for GRAS, companies may consider expanding the intended uses and expanded use levels, provided safety requirements are met.

Note: All data in this document are as of December 31, 2025, and are sourced from publicly available information on the FDA platform. For reference only.

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