アミノ酸の安全性

Safety Studies of Amino Acids in Animals

Indispensable Amino Acids
Amino Acid		Animal	Method of administration	Duration (recovery period)	Dose	Reference
	L-histidine	Fischer rat	Mixed food	13W	0.31, 0.62, 1.25, 2.5, 5% (w/w)	[Japanese] Bull Natl Ins Health Sci (1994), 112:57-63 "13-week subchronic toxicity study of L-histidine monohydrochloride in F344 rats" Ikezaki S, Nishikawa A, et al.
	L-isoleucine	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5% (w/w)	Int J Toxicol (2004), 23(2):119-126 “Thirteen-week oral toxicity study of branched-chain amino acids in rats” Tsubuku S, Hatayama K, et al.
	L-leucine	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5% (w/w)	Int J Toxicol (2004), 23(2):119-126 “Thirteen-week oral toxicity study of branched-chain amino acids in rats” Tsubuku S, Hatayama K, et al.
	L-lysine/HCl	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5% (w/w)	Int J Toxicol (2004), 23(2):113-118 “Thirteen-week oral toxicity study of L-lysine hydrochloride in rats” Tsubuku S, Mochizuki M, et al.
	L-methionine	Fischer rat ♂	Mixed food	4W	0.1, 0.3, 0.9, 2.7% (w/w)	Int J Toxicol (2015), 34(3):233-241 "A 4-week toxicity study of methionine in male rats" Chin K, Toue S, et al.
	L-phenylalanine	SD rat	Mixed food	28 days	0.5, 1.5, 5.0%	Fund Toxicol Sci (2014), 1(2):29-38 "28-Day dietary toxicity study of L-phenylalanine in rats" Shibui Y, Miwa T, et al.
	L-threonine	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5.0%	Fund Toxicol Sci (2014), 1(2):49-62 "A 13-week feeding toxicity study of L-threonine in rats with a recovery period of 5 weeks" Aoki M, Ishida S, et al.
	L-tryptophan	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5.0%	J Appl Toxicol (2018), 38(4): 552-563 "Thirteen week toxicity study of dietary L‐tryptophan in rats with a recovery period of 5 weeks" Shibui Y, Matsumoto H, et al. +LOAEL(mg/kg/day) was calicurated using original research data (BW for LOAEL).
	L-valine	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5% (w/w)	Int J Toxicol (2004), 23(2):119-126 “Thirteen-week oral toxicity study of branched-chain amino acids in rats” Tsubuku S, Hatayama K, et al.
Dispensable Amino Acids
	L-alanine	SD rat	Gavage	4W (2W)	2,000mg/kg/day	Fund Toxicol Sci (2014), 1(2):63-72 “A 4-week oral toxicity study of L-alanine in rats with a recovery period of 2 weeks” Aoki M, Mochizuki M, et al.
	L-arginine	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5% (w/w)	Int J Toxicol (2004), 23(2):101-105 “Thirteen-week oral toxicity study of L-arginine in rats” Tsubuku S, Hatayama K, et al.
		Pig	Mixed food twice a day	13W	1.21, 1.81, 2.42% (w/w)	Amino Acids (2015), 47(5):925-936 “Safety of long-term dietary supplementation with L-arginine in pigs” Hu S, Li X, et al.
		Pig	Mixed food twice a day	13W	1.0, 1.5, 2.0% (w/w)
		SD rat	Drinking water	13W	2.18, 4.35 g/kg/day	Amino Acids (2015), 47(9):1909-1920 “Safety of long‑term dietary supplementation with L‑arginine in rats” Yang Y, Wu Z, et al.
	L-asparagine	Fischer rat	Mixed food	90 days	1.25, 2.5, 5% (w/w)	Food Chem Toxicol (2008), 46(7):2568-2572 "A 90-day toxicity study of L-asparagine, a food additive, in F344 rats" Yokohira M, Hosokawa K, et al.
	L-aspartic acid	Fischer rat	Mixed food	90 days	0.05, 1.25, 2.5, 5.0% (w/w)	Food Chem Toxicol (2008), 46(8):2789-2795 "Toxic effects of L-aspartic acid at high dose levels on kidneys and salivary glands in Fischer 344 rats detected in a 90-day feeding study" Tada Y, Yano N, et al.
	L-cysteine	SD rat	Gavage	4W	500, 1000, 2000 mg/kg/day	J Toxicol Pathol (2017), 30(3):217-229 "Comparisons of L-cysteine and D-cysteine toxicity in 4-week repeated-dose toxicity studies of rats receiving daily oral administration" Shibui Y, Sakai R, et al.
	L-glutamate	-	-	-	-	Acceptable daily intake (ADI) is not specified in JECFA report. ADI can be driven from NOAEL, so that NOAEL of L-Glu/Na is not also specified.: Principles for the safety assessment of food additives and contaminants in food. World Health Organization International Program on Chemical Safety in Cooperation with the Joint FAO/WHO Expert Committee on Food Additives, Geneva, Environmental Health Criteria 70 (1987).
	L-glutamate	CD-1 mouse	Mixed food	3-genaration reproductive toxicity: F0：Gestation & lactation F1: Postweaning – Lactation F2: Postweaning – Lactation F3: Birth - Weaning	1.0, 4.0% (w/w)	Glutamic Acid: Advances in Biochemistry and Physiology, ed. by Filer LJ, et al., Raven Press, NY (1979):231-253 “In utero and dietary administration of monosodium L-glutamate to mice: Reproductive performance and development in a multigeneration study” Anantharaman K
	L-glutamine	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5% (w/w)	Int J Toxicol (2004), 23(2):107-112 “Thirteen-week oral toxicity study of L-glutamine in rats.” Tsubuku S, Hatayama K, et al.
	L-glycine	SD rat	Gavage	28 days	500, 1000, 2000 mg/kg/day	J Toxicol Pathol (2013), 26(4) 405–412, 2013 "A 4-week repeated dose toxicity study of glycine in rats by gavage administration" Shibui Y, Miwa T, et al.
	L-proline	Fischer rat	Mixed food	90 days	0.625, 1.25, 2.5, 5.0%	Regul Toxicol Pharmacol (2010), 58(1):114-120 "Toxicological evaluation of L-proline in a 90-day feeding study with Fischer 344 rats" Tada Y, Yano N, et al.
	L-serine	SD rat	Gavage	13W	500, 1500, 3000 mg/kg/day	Food Chem Toxicol (2009), 47(9):2356-2360 "A 13-week subchronic oral toxicity study of L-serine in rats" Kaneko I, Han L, et al.
	L-serine	Fischer rat	Mixed food	90 days	0.06, 0.5, 1.5, 5.0%	J Toxicol Pathol (2010), 23(1):39-47 "A 90-day feeding toxicity study of L-serine in male and female Fischer 344 rats" Tada Y, Yano N, et al.
	L-tyrosine	SD rat	Gavage	13W	200, 600, 2000 mg/kg/day	Food Chem Toxicol (2016), 87:55-64 "13-week repeated dose toxicity study of l-tyrosine in rats by daily oral administration" Shibui Y, Manabe Y, et al.
Non-code protein Amino Acids
	L-ornithine	SD rat	Mixed food	13W (5W)	1.25, 2.5, 5.0%	Regul Toxicol Pharmacol (2013), 67(3):360-71 "Genotoxicity and subchronic oral toxicity of L-ornithine monohydrochloride" Ishida S, Sarada M, et al.
	L-citrulline	SD rat	Gavage	4W	2000 mg/kg/day	Fund Toxicol Sci (2017), 4(5):219-227 "A 4-week oral gavage toxicity study of L-citrulline in rats" Morita M, Yamaguchi T, et al.
	L-hydroxyproline	SD rat	Gavage	28 days (14 days)	40, 200, 1000, 4000 mg/kg/day	Fund Toxicol Sci (2019), 6(3):65-74 “Twenty-eight-day oral toxicity study of L-hydroxyproline in rats with 14-day post-treatment observation period” Akiduki S, Kawada Y, et al.

Safety Studies of Amino Acids in Human

Review
Amino Acid		[L1]: Safety Assessment Study	[L2]: Safety Review	[L3] Case Study (short term, one dose, etc)
			Advances in Nutrition (2023), S2161-8313(23)00289-2, Elango R.
Indispensable Amino Acids
	L-histidine	American Journal of Clinical Nutrition (2020), 112(5): 1358-1367, Gheller ME, et al.	The Journal of Nutrition (2020), 150(Suppl1), 2588S-2592S, Thalacker-Mercer AE, et al. The Journal of Nutrition (2020) 150(Suppl1):2606S-2608S, Cynober L, et al.
	L-isoleucine
	L-leucine	American Journal of Clinical Nutrition (2012), 96(8):759-767, Elango R, et al.	The Journal of Nutrition (2016), 146(12):2652S-2654S, Cynober L, et al. The Journal of Nutrition (2012), 142(12):2220S-2224S, Pencharz PB, et al.
	L-lysine/HCl		Amino Acids (2019), 51(4):647-659, Hayamizu K, et al. The Journal of Nutrition (2020) 150(Suppl) 1):2606S-2608S, Cynober L, et al.
	L-methionine	American Journal of Clinical Nutrition (2017) 106(2):675-683, Deutz NEP, et al.	The Journal of Nutrition (2020) 150(Suppl 1):2606S-2608S, Cynober L, et al.	Nutrition(2002), 21(2):151-156, Krupkova-Meixnerova L, et al. Revista de Investigacion Clinica (2013), 65(4):323-330, Majluf-Cruz A, et al.
	L-phenylalanine	Nutrients (2021) 13(6): 1976, Miura, et al.	Amino Acids (2021) 53(9):1313-1328, Blachier F, et al.	Journal of the International Society of Sports Nutrition (2017), 14:34, Ueda K, et al.
	L-threonine			Clinical neuropharmacology (1991), 14(5):403-412
				Acta Neurologica Scandinavica (1993), 88(5):334-338
				Neurology (1996), 47(5):1220-1226
	L-tryptophan	The Journal of Nutrition (2013), 143(6):859-866, Hiratsuka C, et al.	The Journal of Nutrition (2016), 146(12): 2652S-2654S, Cynober L, et al.
	L-valine
Dispensable Amino Acids
	L-alanine
	L-arginine	Amino Acids (2018), 50(1):1215-1229, McNeal CJ, et al	The Journal of Nutrition (2016), 146(12): 2652S-2654S, Cynober L, et al. Regulatory Toxicology and Pharmacology (2008), 50(3):376-399, Shao A, et al.
	L-asparagine
	L-aspartic acid			Metabolism (1989), 38(2):1179-l 182
	L-cysteine			Metabolism (1989), 28(12):1179-1182
	L-glutamate			Acceptable daily intake (ADI) is not specified in JECFA report. ADI can be driven from NOAEL, so that NOAEL of L-Glu/Na is not also specified. : Principles for the safety assessment of food additives and contaminants in food. World Health Organization International Program on Chemical Safety in Cooperation with the Joint FAO/WHO Expert Committee on Food Additives, Geneva, Environmental Health Criteria 70 (1987).
	L-glutamine	Journal of Parenteral and enteral nutrition (2004) 28(2):65-75, Rathmacher JA, et al.	Regulatory Toxicology and Pharmacology (2008), 50(3):376-399, Shao A, et al.	Nutrients (2020) 12(10):E2953, Ogden HB, et al.
	Glycine	Journal of Urban Living and Health Association (2006), 50(1):27-32, Inagawa K, et al.
	L-proline
	L-serine	Nutrients (2021) 13(6): 1976, Miura, et al.	Amino Acids (2021) 53(9):1313-1328, Blachier F, et al.
	L-tyrosine			Hypertension (1985), 7(4):593-596
				The Lancet (1989), 334(8671):1067-1069
				Aviation, Space and Environmental Medicine (1995), 66(4):313-319
				Journal of Child Neurology (2008),23(6):609-13
Non-code protein Amino Acids
	L-ornithine/HCl	Amino Acid (2022); 1-13, Miura et al.		Nutrition Research (2008), 28(11):738-743
	L-citruline	Amino Acid (2022); 1-13, Miura et al.		British Journal of Nutrition (2008), 99(4):855-862
	L-hydroxyproline