Table 4.

Suggested health-promoting effects, toxicological data, safety assessments and regulatory status of selected natural antimicrobial compounds with antibacterial activity against Cronobacter spp. in PIF.

NAC	Reported Health Benefits	Toxicology/safety assessments	Regulatory status
Cocoa powder	Prevention of cardiovascular disease; improved blood pressure regulation, insulin resistance and vascular function; increased production of nitric oxide (NO) and antioxidant effects including delayed oxidation of low-density lipoprotein cholesterol, inhibition of ultraviolet-induced DNA oxidation (113).	Chronic dietary exposure not carcinogenic to rats (114); No evidence of toxic effects on the heart, liver, kidney, lungs, testis, and spleen of rats fed high oral doses (115).	Food ingredient.
Polyphenolic tea extracts	Black teas: prevention of cancer; obesity, antioxidant protective and anti-hyperglycemic effects (116). Green teas: prevention of cancer, obesity, metabolic syndrome, type 2 diabetes, cardiovascular diseases (117).	Suspected cytotoxicity of epigallocatechin 3-gallate, the major catechin present in green tea, in adults and children (117, 118).	Generally Recognized as Safe (GRAS) according to US Code of Federal Regulations (USCFR), Title 21, § 182.20, Essential oils, oleoresins (solvent-free), and natural extractives (including distillates (119). Listed as dietary supplements under the Health and Education Act of 1994 (120).
Cinnamon essential oil, trans-cinnamaldehyde	Antitumour, anti-inflammatory and analgesic, anti-diabetic and anti-obesity, antibacterial and antiviral, cardiovascular protective, cytoprotective, neuroprotective, and immunoregulatory effects (121); Treatment of high blood glucose and lipid levels and other symptoms of the metabolic syndrome, polycystic ovary syndrome (PCOS) and inflammatory disorders (122).	Occasional gastrointestinal disorders and allergic reactions reported (121); Potential nephrotoxicity and hepatotoxicity at higher than recommended daily dose (123).	Trans-cinnamaldehyde: USCFR GRAS, § 182.60.
Vanillin, ethyl vanillin, vanillic acid	Antioxidant, anti-inflammatory, antisickling, antimicrobial, and hypolipidemic effects; prevention of cancer, periodontal disease, and bone deterioration (124)	Lack of toxicity at approved levels of intake in foods; Vanillin may induce bronchoconstriction in asthmatics (125), contact dermatitis at high concentrations (126).	Vanilla extracts: USCFR GRAS, §182.20; Vanillin and ethyl vanillin: USCFR GRAS §182.60 (Synthetic flavoring substances and adjuvants, can be from natural sources); Vanillic acid is not listed in the US FDA Code of Federal Regulations; evaluation by the FAO/WHO Expert Committee on Food Additives (JECFA no. 959) yielded “no safety concern at current levels of intake when used as a flavoring agent” (127).
Caprylic acid	Role in the prevention of infection and inflammation as part of lipid emulsions used in parenteral feeding of neonates (128); Prevention of obesity by decreasing energy intake, possible effects on appetite (129).	No evidence of toxic effects at doses up to 10% in the diet (130).	USCFR GRAS §184.1025; Available as a dietary supplement.
Thymoquinone	Anti-inflammatory, antimicrobial, antiparasitic, antioxidant, antihyperglycemic, and anticancer properties (131).	Concentration dependant in vitro hepato-toxic effects (132); No evidence of cytotoxicity in rats (133); no evidence of toxicity in humans at daily oral doses up to 28 g/kg (134).	Source plant (Nigella sativa L., black seed or black cumin), is listed by USCFR GRAS in § 182.10 (Spices and other natural seasonings and flavorings); Source plant extracts listed as dietary supplements under the Health and Education Act of 1994 (120).
Coenzyme Q0	Antitumor, anti-inflammatory and anti-angiogenic effects (82).	No evidence of toxicological effects from dietary supplements (135).	Not presently permitted as a food additive. Available as a dietary supplement.
Nisin	Prevention of dental caries (136); anticancer and antibacterial (137).	Effects on the cytoskeleton of keratinocytes derived from normal epithelium; increased blood cholesterol concentrations in rats (138).	USCFR GRAS, §184.1538, antimicrobial for specified uses which do not currently include PIF.
Lactoperoxidase	Inactivation of carcinogens (139); Contributions to cytotoxic effects against human cancer cells (140); Prevention of bone resorption through osteoclastogenesis (141).	Preparations derived from bovine milk could contain proteins which may be allergenic for sensitive individuals.	USCFR GRAS notice granted for lactoperoxidase system as a processing aid for dairy products pursuant to § 170.30 (Eligibility for classification as generally recognized as safe (GRAS).
Bovine lactoferrin	Contributions to cytotoxic effects against human cancer cells (139, 142); Contribution to gut health and immune development in neonates (143, 144); Prevention of acute gastrointestinal and respiratory symptoms in children aged 12–32 months (145).	No adverse effects in rats fed 2,000 mg/kg/day bovine lactoferrin for 13 days (146); Considered safe for human consumption (147).	USCFR GRAS notice granted for cow's milk-derived lactoferrin as an additive ingredient for PIF pursuant to §170.35 (Affirmation of generally recognized as safe (GRAS) status).
Cell free extracts of Lactobacillus spp.	Variable, depending on species and nature of extracts; Management of intestinal, respiratory diseases (148); Cytotoxic effects against human cancer cells (149); Immunomodulation, anti-inflammatory, antiproliferative, hepatoprotective effects (97).	No evidence of adverse effects from oral use.	USCFR GRAS notices have been granted for some cell free extracts; Several are available as a dietary supplements.