Safety assessment of the biotechnologically produced human-identical milk oligosaccharide 3-Fucosyllactose (3-FL)

Pitt, Jeffrey A.; Chan, Melissa P. L.; Gibson, Christopher; Hasselwander, Oliver; Lim, Andrew; Mukerji, Pushkor; Mukherjea, Ratna; Myhre, A.; Sarela, P.; Tenning, P.; Himmelstein, Matthew W.; Roper, Jason M.

doi:10.1016/j.fct.2019.110818

Cited by 18 publications

(16 citation statements)

References 43 publications

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“…In this study, administration of HMO MIX 1 to neonatal farm piglets up to 8.0 g/L was not associated with any adverse outcomes. The lack of adverse effects in genotoxicity and sub-chronic studies conducted in rat with HMO Mix 1, 7 the safety of the individual oligosaccharides demonstrated with other safety studies, 8 –19 and the results of this study support the safety of this ingredient in infant formulas, including those consumed during the sensitive period of human development below 12 weeks of age.…”

Section: Discussionsupporting

confidence: 76%

“…7 In these previous studies, HMO MIX 1 was demonstrated to be non-genotoxic and produced no adverse effects in animals at 10% of the diet, for a calculated dose of 5.67 g/kg and 6.97 g/kg in male and female rats, respectively. Other safety studies have been conducted on the individual HMOs in this novel mixture: 2′-FL, 8 –10 3-FL, 11 LNT, 12 3′-SL, 13,14 and 6′-SL, 15,16 including previous studies in neonatal piglets for 2′-FL 17 and 3′-SL. 18,19 These previous studies and the long history of exposure via human milk at the concentrations intended to be added to infant formula strongly support the safety of these oligosaccharides to human infants.…”

Section: Introductionmentioning

confidence: 99%

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A safety evaluation of mixed human milk oligosaccharides in neonatal farm piglets

Hanlon

2020

Toxicology Research and Application

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Human Milk Oligosaccharides (HMOs) are the third most abundant, solid component of human milk after lactose and fat. As novel processes are developed to cost-effectively produce commercial volumes of these oligosaccharides, they are becoming more common components of infant formulas worldwide. The study evaluated the safety of a novel mixture of HMOs in a neonatal piglet model with the objective of identifying potential effects during the sensitive, preweaning developmental stage of life. The mixture of HMOs (HMO MIX 1) was composed of 2′-fucosyllactose (2′-FL), 3-fucosyllactose (3-FL), lacto-N-tetraose (LNT), 3′-sialyllactose (3′-SL), and 6′-sialyllactose (6′-SL), and was administered to 2-day old piglets at either 5.75 or 8.0 g/L for a period of 21 days. Piglets in the 5.75 and 8.0 g/L HMO MIX 1 dosing groups did not exhibit differences in body weight, food consumption, or feed efficiency. Analysis of clinical chemistry parameters on Study Day 7 and Study Day 21 did not demonstrate any effects that could be attributed to HMO MIX 1, nor were there any findings in organ weight, macroscopic, or microscopic inspection of tissues that could be attributed to this oligosaccharide blend. Therefore, since administration of HMO MIX 1 in a liquid diet up to 8.0 g/L resulted in no toxicologically-relevant effects in comparison with animals fed a control diet, this study supports the safety of this ingredient for addition to infant formula products.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

A safety evaluation of mixed human milk oligosaccharides in neonatal farm piglets

Hanlon

2020

Toxicology Research and Application

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“…The bacteria affected the metabolism of nutrient fiber, which was conducive for defecation (Konikoff and Gophna, 2016). Comparison to several HMOs currently approved as ingredients and infant formula/follow-on formula uses indicates that LOS has the similar safety profile, based on the current studies presented here (Coulet et al, 2013;Phipps et al, 2018;Pitt et al, 2019). No evidence of toxicity was observed and in the absence of compound-related adverse effects in the study.…”

Section: Motlin Gastrin Endothelin Somatostatin Acetylcholine Enzmentioning

confidence: 57%

Lotus seed oligosaccharides at various dosages with prebiotic activity regulate gut microbiota and relieve constipation in mice

Chen

Miao

et al. 2019

Food and Chemical Toxicology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…LNFP-I/2 0 -FL was negative in both of the in vitro genotoxicity studies, which is to be expected given the absence of any structural alerts for HMOs and no reports of genotoxicity in previous studies with related compounds. In a safety assessment of another HiMO (3-FL) produced biotechnologically, negative results were reported in the bacterial reverse mutation test and chromosome aberration test, but the outcome of the in vitro mammalian cell micronucleus test was equivocal (Pitt et al, 2019). A negative result in a follow-up in vivo mammalian erythrocyte micronucleus test confirmed that 3-FL was nongenotoxic overall.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity and neonatal subchronic toxicity assessment of a novel mixture of the human‐identical milk oligosaccharides lacto‐N‐fucopentaose I and 2′‐fucosyllactose

Phipps

Lynch

Stannard

et al. 2020

J of Applied Toxicology

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Human milk oligosaccharides (HMOs) are a complex group of bioactive molecules largely observed in human breast milk but also occurring in limited amounts in other mammalian milks. Advances in biotechnology have enabled production of humanidentical milk oligosaccharides (HiMOs), structurally identical molecules to HMOs found naturally in human milk, intended for addition to infant formula to more closely replicate breast milk. Biosynthesis of a novel mixture of two major HMOs, lacto-N-fucopentaose I and 2 0-fucosyllactose (LNFP-I/2 0-FL), recently became possible. To support the safety of LNFP-I/2 0-FL for use in infant formula and other foods, it was subject to a safety assessment comprising a bacterial reverse mutation test, an in vitro mammalian cell micronucleus test, and a 90-day oral gavage study in neonatal rats. In the 90-day study (the first HiMO study to include the new endocrinesensitive endpoints described in the 2018 version of OECD Test Guideline 408), LNFP-I/2 0-FL was administered by oral gavage to neonatal rats once daily (from Day 7 of age) for 90 consecutive days, at doses up to 5000 mg/kg bw/day, followed by a 4-week recovery period. Concurrent reference controls received 5000 mg/kg bw/day of the approved infant formula ingredient oligofructose. LNFP-I/2 0-FL was nongenotoxic in vitro. The highest dose tested (5000 mg/kg bw/day) was established as the no-observed-adverse-effect level in the 90-day study, as there were no test article-related adverse effects on clinical observations, body weight, food consumption, clinical pathology, and organ weights nor any noteworthy macroscopic or microscopic findings. This supports the safety of LNFP-I/2 0-FL for its intended uses in food.

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Safety assessment of the biotechnologically produced human-identical milk oligosaccharide 3-Fucosyllactose (3-FL)

Cited by 18 publications

References 43 publications

A safety evaluation of mixed human milk oligosaccharides in neonatal farm piglets

A safety evaluation of mixed human milk oligosaccharides in neonatal farm piglets

Lotus seed oligosaccharides at various dosages with prebiotic activity regulate gut microbiota and relieve constipation in mice

Genotoxicity and neonatal subchronic toxicity assessment of a novel mixture of the human‐identical milk oligosaccharides lacto‐N‐fucopentaose I and 2′‐fucosyllactose

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