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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Objective of study:
bioaccessibility (or bioavailability)
toxicokinetics
Qualifier:
according to guideline
Guideline:
other: US Food and Drug Administration Redbook II Guidelines (FDA, 1993).
GLP compliance:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
deionised
Duration and frequency of treatment / exposure:
90 days once daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
600 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose / concentration:
treated animals: 12
contols: 6
Control animals:
yes, concurrent vehicle
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): blood
- Time and frequency of sampling: Blood samples taken from 3 animals/sex/dose, at time 0 (immediately prior to dosing), 1, 2, 4, 8 and 24 hours following dosing on days 0 and 90 of the study for estimation of plasma taurine levels. Blood samples were collected from concurrent controls (6 animals/sex) on the same days at 0, 2 and 8 hours following dosing with vehicle.
Key result
Test no.:
#1
Toxicokinetic parameters:
Cmax: at around 1 hour after dosing
Key result
Test no.:
#1
Toxicokinetic parameters:
other: Generally returning to baseline values by 24 hours. Plasma concentrations 24 hours after dosing were comparable with control values both on study day 0 and on day 90.
Key result
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: less than 1 hour
Remarks:
initial half life
Key result
Test no.:
#1
Toxicokinetic parameters:
half-life 2nd: Plasma taurine levels 2 hours after dosing were 21-51% of the values measured at one hour.
Key result
Test no.:
#1
Toxicokinetic parameters:
half-life 3rd: ranged from 8.7 to 40 hours.
Remarks:
terminal half-life
Key result
Test no.:
#1
Toxicokinetic parameters:
AUC: Values were similar on study days 0 and 90.
Metabolites identified:
not specified
Conclusions:
In the toxicokinetic study, plasma taurine levels increased in a dose-related manner, reaching peak Cmax values at around 1 hour after dosing and generally returning to baseline values by 24 hours.
Plasma taurine levels 2 hours after dosing were 21-51% of the values measured at one hour. Initial half-life was less than 1 hour and terminal half-life ranged from 8.7 to 40 hours.
Plasma concentrations 24 hours after dosing were comparable with control values both on study day 0 and on day 90. Area under the plasma-time concentration curve (AUC) values were similar on study days 0 and 90.
Both Cmax and AUC were proportional to dose. This study showed that taurine is readily bioavailable following oral administration and that it does not accumulate.

Description of key information

In the toxicokinetic study, plasma taurine levels increased in a dose-related manner, reaching peak Cmax values at around 1 hour after dosing and generally returning to baseline values by 24 hours.

Plasma taurine levels 2 hours after dosing were 21-51% of the values measured at one hour. Initial half-life was less than 1 hour and terminal half-life ranged from 8.7 to 40 hours.

Plasma concentrations 24 hours after dosing were comparable with control values both on study day 0 and on day 90. Area under the plasma-time concentration curve (AUC) values were similar on study days 0 and 90.

Both Cmax and AUC were proportional to dose. This study showed that taurine is readily bioavailable following oral administration and that it does not accumulate.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100

Additional information

Assessment of the Toxicokinetic Behaviour of Taurine (CAS 107-35-7; EC 203-483-8)

 

Taurine, 2-aminoethanesulfonic acidwith a molecular weight of 125.14 g/mole is a white crystalline powder that is almost odourless but with a slightly acidic taste and is very soluble in water (79 g/L) (see chapter 4.8 water solubility).The measured log Po/w is -1.30 (see chapter 4.7 partition coefficient), indicating the hydrophilie and that a general accumulation of Taurine is not given.

Taurine occurs naturally in food, especially in seafood and meat, and it is a normal metabolite in humans. It is a metabolic product of sulphur-containing amino acids, and it is mainly biosynthesised from cysteine in the liver (SCF, 1999).The major route for the biosynthesis of taurine is from methionine and cysteine via cysteinesulfinic acid decarboxylase (CSD), and typically requires oxidation of hypotaurine to taurine as the final step.The enzyme cysteine dioxygenase (CDO) catalyzes the conversion of L-cysteine to cysteine sulfinate, and the oxidation of hypotaurine (2-aminoethane sulfinate) results in taurine. (Stipanuk, 1986)

 

There are some data on the toxicokinetic properties of Taurin available.

 

Absorption, Distribution, Metabolism, Excretion

 

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2012).

 

The smaller the molecule, the more easily it will be taken up. In general, molecular weights below 500 g/mol are favourable for oral absorption (ECHA, 2012). As the molecular weight of Taurine is 125.14 g/mol and as it is very soluble in water absorption of this molecule in the gastrointestinal tract is given. Taurine is a highly polar and lipophobic compound; hence passive diffusion of taurine through the cell wall is limited. The predominant route of absorption into enterocytes is via transporters. (EFSA Journal 2012)

Several human data show that Taurine is absorbed via the small intestine and transported to the liver before being released into circulation. It can enter cells via an active transporter, which then responds to the intracellular concentration. A high taurine concentration downregulates the taurine transporter and taurine is excreted by the kidneys; reabsorption into the renal tubules occurs if taurine concentration is low. (Wójcik, et al., 2010; Ahlman et al., 1993, 1995a,b).

The cells have specific Na+/Cl–-dependent carriers (TauT), which allow maintenance of a high intracellular to extracellular taurine ratio. (Ripps and Shen, 2012) The concentration of taurine in tissues is independent of dietary supplementation.

As a nutrient, taurine is conjugated with bile acids in the liver, and also is required for cell membrane stabilization, osmoregulation, regulation of calcium flux, neuronal excitability, and may have anti-oxidant functions (Eudy et al., 2013).

In overdose in rats, taurine was rapidly absorbed and then rapidly excreted in urine. The data indicate that exogenous taurine rapidly equilibrates with endogenous body pools and that any excess is rapidly eliminated by the kidneys (Sved et al., 2007).

 

The possible accumulation of taurine has also been investigated. The rat toxicokinetic study conducted by WIL Research Laboratories only sampled on study days 0 and 90 but the results did not indicate any accumulation (WIL, 2001a). These data are in accordance with findings from the limited published data on humans. Human studies showed significant increases in plasma taurine 90 minutes after consumption of a taurine-rich meal with levels declining to background within 180-270 minutes (Trautwein and Hayes, 1995). These results also corroborate those from an unpublished human study by Taisho Pharmaceuticals, using radiolabelled taurine, which showed peak serum levels at 1-2 hours after oral administration, declining by 7 hours (Watanabe, cited in Red Bull GmbH, 2001).

 

Physiological taurine status is determined by dietary intake and from endogenous synthesis.Taurine is a produced in the body from methionine and cysteine metabolism. This means it is a degradation product of these sulfur-containing amino acids(Stipanuk, 1986).Mammals are capable only of sulfur oxidation, not reduction. (Huxtable, 1992)

It is assigned to the conditionally essential amino acids because it isnot incorporated into proteinsin the human body. Taurine occurs mainly in free, unbound form (Ripps und Shen, 2012).

In mammals, taurine is synthesised in many tissues; the main sites are liver, brain (Huxtable, 1992) and pancreas, predominantly inα-islets (Bustamante et al., 2001).

In mammals, taurine is near ubiquitous in distribution, with tissue concentrations typically in the micromole per gram wet weight range. Body fluids, such as plasma, cerebrospinal fluid, and extracellular fluid, contain much lower concentrations, typically in the range of 10-100 µM. (Huxtable, 1992). High concentrations of taurine are present in retina, liver, pancreas, central nervous system and white blood cells. The largest pools of taurine are found in skeletal and cardiac muscles, where it regulates intracellular Ca2+ concentration (Szymanska and Winiarska, 2008).

Taurine is synthesised from cysteine and methionine in a few steps, one of which requires pyridoxal-5′-phosphate (vitamin B6) as coenzyme of cysteine sulphinate decarboxylase.

Taurine is chemically inert. It is biochemically inert in animals in the sense that the greatest proportion of taurine is excreted unchanged. In most species, cell, organ, and whole-body taurine concentrations are regulated by transport, biosynthesis and metabolism being of minor import.

Taurine is excreted as such or in the form of taurocholate or related bile salts. (Huxtable, 1992)

 

In summary:

Following oral exposure in rodents and humans, taurine is rapidly absorbed via a 13-amino acid or taurine active transport system in the small intestine (Sved et al., 2007; Ghandforoush-Sattari et al., 2010). In healthy, fasted human volunteers, maximum plasma levels of 0.47 to 0.90 mmol/L were attained within 1 to 2.5 hours following a taurine-rich meal or single oral dose of 4 g taurine (Trautwein and Hayes, 1995). Taurine has a plasma half-life of 0. 7 to 1.4 hours, with plasma taurine concentrations in humans reported to return to baseline within 7 hours of consumption (Trautwein and Hayes, 1995; Ghandforoush-Sattariet al.,2010). Taurine is therefore not expected to bioaccumulate, even in individuals consuming unusually large amounts of taurine on a daily basis. This is illustrated by the marginal increases in plasma taurine concentrations reported within 12 to 24 hours of the last dose of taurine in subjects consuming 3 or 6 g taurine/day for 8 weeks or 7 days (respectively) (Zhang et al., 2004a; Rosa et al., 2014). Although these increases (approximately 71 and 97% in the 7-day and 8-week studies, respectively) were statistically significant, they are considered to be physiologically marginal compared to an increase of approximately 933% reported 1 hour after consumption of 4 g taurine in humans (Ghandforoush-Sattari et al.,2010).

Overall, the available data demonstrate that approximately 36 to 67% of orally administered taurine is rapidly absorbed from the gastrointestinal tract, following which it may be conjugated with bile acids and excreted through the biliary tract. Unconjugated taurine is widely distributed and rapidly equilibrated, with any excess taurine eliminated primarily via the kidneys.

 

Literature:

 

Ahlman B, Leijomarck CE, Wernerman J (1993). The content of free amino acids in the human duodenal mucosa. Clinical Nutrition 12 (5): 266-271.

Ahlman B, Ljungqvist O, Andersson K, Wernerman J (1995a). Free amino acids in the human intestinal mucosa; impact of surgery and critical illness. Clinical Nutrition 14 (1): 54 - 55.

Ahlman B, Ljungqvist O, Persson B, Bindslev L, Wernerman J (1995b). Intestine amino acid content in critically ill patients. Journal of Parenteral and Enteral Nutrition 19 (4): 272- 278.

Bustamante J, Lobo MV, Alonso FJ, Mukala NT, Giné E, Solís JM, Tamarit-Rodriguez J and Martín Del Río R, 2001. An osmotic-sensitive taurine pool is localised in rat pancreatic islet cells containing glucagon and somatostatin. American Journal of Physiology, Endocrinology and Metabolism, 281, E1275–1285.

EFSA, 2012. SCIENTIFIC OPINION Scientific Opinion on the safety and efficacy of taurine as a feed additive for all animal species. EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP). EFSA Journal 2012;10(6):2736

Ghandforoush-Sattari M, Mashayekhi S, Krishna Channarayapatna V, Thompson JP, Routledge PA (201 0). Pharmacokinetics of oral taurine in healthy volunteers. J Amino Acids 2010.

Huxtable RJ, 1992. Physiological actions of taurine. Physiology Review, 72, 101–163.

Red Bull GmbH (2001). Red Bull® Energy Drink. Submission to the European Commission by Red Bull GmbH, Brunn 115, A-5330 Fuschl am See, Austria, 31 December 2001.

Ripps und Shen (2012).Review: Taurine: A “very essential” amino acid. Molecular Vision 18: 2673-2686

Rosa FT, Freitas EC, Deminice R, Jordao AA, Marchini JS (2014). Oxidative stress and inflammation in obesity after taurine supplementation: a double-blind, placebo-controlled study.Eur J Nutr 53(3): 823-830.

SCF (Scientific Committee on Food), 1999. Opinion on caffeine, taurine and D-glucurono-γ-lactone as constituents of so-called “energy” drinks, adopted on 21 January 1999. Minutes of the 115th Meeting of the Scientific Committee on Food held on 20-21st January 1999. European Commission DG Consumer Policy and Consumer Health Protection. Document XXIV/2146/99.

Stipanuk MH. Metabolism of sulfur-containing amino acidsAnnu Rev Nutr6: 179–209. 1986.

Sved DW, Godsey JL, Ledyard SL, Mahoney AP, Stetson PL, Ho S, Myers NR, Resnis P and Renwick AG, 2007. Absorption, tissue distribution, metabolism and elimination of taurine given orally to rats. Amino Acids, 32, 459–466.

Szymanska K and Winiarska K, 2008. Taurine and its potential therapeutic application. Postępy Higieny Medycyny Doświadczalnej, 62, 75–86.

Trautwein EA, Hayes KC (1995). Plasma and whole blood taurine concentrations respond differently to taurine supplementation (humans) and depletion (cats). Z. Ernährungswiss 34: 137 -142.

WIL (2001a). A 13-week oral (gavage) toxicity study of taurine in rats. Final Report, December 26, 2001, WIL-423002. WIL Research Laboratories Inc., Ohio, USA. Submitted to the European Commission by Red Bull GmbH, Brunn 115, A-5330 Fuschl am See, Austria, 31 December 2001.

Wójcik OP, Koenig KL, Zeleniuch-Jacquotte A, Costa M, Chen Y. The potential protective effects of taurine on coronary heart disease. Atherosclerosis. 2010; 208(1):19-25.

Zhang M, Bi LF, Fang JH, Su XL, Da GL, Kuwamori T (2004a). Beneficial effects of taurine on serum lipids in overweight or obese non-diabetic subjects.Amino Acids 26(3):267-271.