アミノ酸の安全性

Safety Studies of Amino Acids in Animals

Amino Acid Animal Method of administration Duration
(recovery period)
Dose Reference
Indispensable Amino Acids
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.
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).
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.
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

Amino Acid [L1]: Safety Assessment Study [L2]: Safety Review [L3] Case Study (short term, one dose, etc)
Review
Advances in Nutrition (2023), 14(4): 885-894, 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