Safety evaluation of the human-identical milk monosaccharide, l-fucose.

l-Fucose is a natural monosaccharide present in mammals where it is found predominantly as an O-glycosidically linked component of glycoproteins, glycolipids, and oligosaccharides. It is also present in its free form in human breast milk (human milk monosaccharide). l-Fucose plays important roles in the development of the immune and nervous systems and is involved in cognitive function and memory formation. The human-identical milk monosaccharide l-fucose is therefore proposed for use in infant formulas to better simulate the free saccharides present in human breast milk. As part of the safety evaluation of l-fucose, a subchronic dietary toxicity study preceded by an in utero phase was conducted in Sprague-Dawley rats. l-Fucose was without maternal toxicity or compound-related adverse effects on female reproduction and general growth and development of offspring at a maternal dietary level up to 1%, equivalent to a dose of 1655 mg/kg body weight (bw)/day. During the subchronic phase, no compound-related adverse effects were observed in first generation rats at dietary levels of up to 1% (highest level tested), corresponding to doses of 516 and 665 mg/kg bw/day in males and females, respectively. l-Fucose was non-genotoxic in a series of in vitro genotoxicity/mutagenicity tests. These results support the safe use of l-fucose in infant formula and as a food ingredient at levels equivalent to those present in human breast milk.

A 3-week pre-clinical study of 2'-fucosyllactose in farm piglets.

One of the most abundant oligosaccharides found in human milk is 2'-fucosyllactose, a trisaccharide composed of fucose and lactose, and multiple studies have demonstrated a health benefit to this compound. Recent advances have allowed for the large-scale production of oligosaccharides via fermentation, including 2'-fucosyllactose. A neonatal piglet model was used to evaluate the tolerability of 2'-fucosyllactose, produced through this process, in order to demonstrate the suitability of this compound for human infants under 12 weeks of age. Crossbred farm piglets, at lactation day 2, were assigned to one of four treatment groups receiving a liquid diet containing 0, 200, 500 or 2000 mg/L of 2'-fucosyllactose. The calculated consumption of 2'-fucosyllactose corresponded to dose levels of 29.37, 72.22 and 291.74 mg/kg/day, respectively, in males and 29.30, 74.31, and 298.99 mg/kg/day, respectively in females. Piglets were administered diet for 3 weeks; and there were no test article-related effects on growth and development (clinical observations, body weight and food consumption), clinical pathology parameters (hematology, clinical chemistry, coagulation and urinalysis), or any histopathologic changes. Therefore, dietary exposure to 2'-fucosyllactose at concentrations up to 2000 mg/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth.

Safety evaluation of the human-identical milk monosaccharide sialic acid (N-acetyl-d-neuraminic acid) in Sprague-Dawley rats.

N-Acetyl-d-neuraminic acid (Neu5Ac) is the predominant form of sialic acid (Sia) in humans, while other mammals express Sia as a mixture with N-glycolyl-d-neuraminic acid (Neu5Gc). Neu5Ac occurs in highest levels in the brain and in breast milk, and is therefore, coined a human-specific milk monosaccharide, and is thought to play an important nutritional role in the developing infant. Synthesized human-identical milk monosaccharide (HiMM) Neu5Ac is proposed for use in infant formulas to better simulate the free saccharides present in human breast milk. As part of the safety evaluation of HiMM Neu5Ac, a subchronic dietary toxicity study preceded by an in utero phase was conducted in Sprague-Dawley rats. Neu5Ac was without maternal toxicity or compound-related adverse effects on female reproduction and on the general growth and development of offspring at a maternal dietary level of up to 2%, equivalent to a dose of 1895mg/kg body weight (bw)/day. During the subchronic phase, no compound-related adverse effects were observed in first generation rats at dietary levels of up to 2% (highest level tested), corresponding to doses of 974 and 1246mg/kgbw/day in males and females, respectively. Neu5Ac also was non-genotoxic in a series of in vitro genotoxicity/mutagenicity tests. These results support the safe use of Neu5Ac both in infant formula and as a food ingredient at levels equivalent to those found naturally in human breast milk.

A 3-week dietary safety study of octenyl succinic anhydride (OSA)-modified starch in neonatal farm piglets.

Octenyl succinic anhydride (OSA)-modified starch functions as both an emulsifier and emulsion stabilizer in foods, and is intended for use in infant formula, follow-on formula, and formulae for special medical purposes. These formulae predominantly include extensively hydrolyzed protein or free amino acids, rather than intact protein, which otherwise would provide emulsifying functionality. The study objectives were to evaluate (1) the safety of OSA-modified starch after three weeks of administration to neonatal farm piglets, beginning 2 days after birth and (2) the impact of OSA-modified starch on piglet growth. OSA-modified starch was added to formula at concentrations of 2, 4, and 20 g/L. The vehicle control, low-dose, and mid-dose diets were supplemented with Amioca™ Powder to balance the nutritional profiles of all formulations. There were no test article-related effects of any diet containing OSA-modified starch on piglet growth and development (clinical observations, body weight, feed consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation, urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). Therefore, dietary exposure to OSA-modified starch at concentrations up to 20 g/L was well tolerated by neonatal farm piglets and did not result in adverse health effects or impact piglet growth.

A 3-week dietary bioequivalence study in preweaning farm piglets of two sources of docosahexaenoic acid produced from two different organisms.

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are components of human breast milk and commonly added to infant formula. The first DHA-containing algal oil for infant formulas was DHASCO® produced from the microalgae Crypthecodinium cohnii. Recently, new DHA-rich oil was obtained from the microalgae Schizochytrium sp., herein named DHASCO-B. The objectives of this study were to evaluate the bioequivalence of DHASCO-B to DHASCO when administered in a blend with ARA oil and the potential effects after 3weeks' administration in milk replacer formula to preweaning farm piglets. DHASCO-B and DHASCO were added to formula at concentrations 0.32% and 0.96% DHA (% of total fatty acids). There were no test article-related effects of any diet on piglet growth and development (clinical observations, body weight, food consumption), or clinical pathology parameters (hematology, clinical chemistry, coagulation and urinalysis). In addition, there were no adverse effects at terminal necropsy (macro- and microscopic pathology evaluations). DHA content in plasma, RBC, heart, liver and brain showed dose-related accumulation and confirmed no differences between corresponding DHASCO-B and DHASCO groups. Therefore, dietary exposure to DHASCO-B and DHASCO was well tolerated by the preweaning piglets during the 3-week dosing period right after birth and DHASCO-B and DHASCO were bioequivalent.

Multigeneration reproductive study of hydroxyprogesterone caproate (HPC) in the rat: laboratory results and clinical significance.

To demonstrate reproductive safety of a new commercial product for reducing the risk of preterm birth, HPC (17α-hydroxyprogesterone caproate, Makena; manufactured by Baxter Pharmaceutical Solutions, Bloomington IN for Ther-Rx Corporation, St. Louis, MO) was administered intramuscularly in Charles River LaboratoryCD strain rats. HPC was given at intervals equal to the half-life measured in rats during three phases of embryo-fetal development: during the period of ovarian development (RP1, days 8, 14, and 20), following implantation of the embryo (TP, days 6, 12, and 18), and, corresponding to the start of the drug in week 16 or later in humans, after gonadal formation including differentiation of the testes (RP2, day 17). Dose levels up to 30× the human therapeutic doses were utilized including 0 (vehicle), 5, 25, and 150 mg/kg (volume 0.6 ml/kg). Four groups of 25 time-mated rats each were used for each phase. In addition, equal numbers of naïve (untreated) rats of opposite gender were used for F(1) breeding studies. HPC did not produce any consistent test-article-related findings in the treated F(0) dams, their developing F(1) fetuses and did not affect the ability of the latter to produce a viable F(2) generation. The F(1) offspring did not evidence any adverse effects during their behavioral, sensory, and developmental assessments, including teratogenicity. Based on the cumulative data obtained from rats treated over two generations and during development in this study, the No-observable-effect-level (NOEL) was established as 150 mg/kg. This study supports the absence of reproductive toxicity with HPC in published studies in animal models and in human clinical trials.