L-Ascorbic acid, 2-(dihydrogen phosphate), sodium salt (1:3)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert Statement

Adequacy of study:

key study

Study period:

2009-03-03

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert Statement based on available Data and Studies. No experimental study conducted.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

425-180-1

EC Name:

-

Cas Number:

66170-10-3

Molecular formula:

C6 H9 O9 P . 3 Na (CAS) C6 H6 Na3 P O9 (Hill)

IUPAC Name:

trisodium mono-(5-(1,2-dihydroxyethyl)-4-oxido-2-oxo-2,5-dihydro-furan-3-yl)phosphate

Details on test material:

- Name of test material: SODIUM ASCORBYL PHOSPHATE
- Physical state: SOLID (POWDER), BEIGE
- Analytical purity: 85.4 G/100 G (HPLC)
- Lot/batch No.: 28600/37-9

Results and discussion

Any other information on results incl. tables

Toxicokinetic Assessment of Sodium ascorbyl phosphate

The substance Sodium ascorbyl phosphate is the tri-sodium salt of the L-Ascorbic acid 2-monophosphate ester. Concerning the toxicological behaviour it can be assumed that Sodium ascorbyl phosphate is hydrolysed to ascorbic acid in the gastrointestinal tract by phosphatases to a great extent. If a resportion of unchanged Sodium ascorbyl phosphate occurs, it is supposed to be also degraded by phosphatases in different tissues and organs. It can be thus concluded that the toxicokinetic behaviour of Sodium ascorbyl phosphate is almost identical with the toxicokinetics of Ascorbic acid, which is described more detailed below. A 28-day oral toxicity study in rats after administration via the drinking water shows that Sodium ascorbyl phosphate respectively Ascorbic acid is available systemically. The findings in the urinary bladder of the animals indicate that the excretion of Sodium ascorbyl phosphate and its metabolites occurs via the urine [4]. Due to the hydrophilic character of Sodium ascorbyl phosphate and Ascorbic acid an accumulation in the body can be excluded. These assumptions are confirmed by experimental data described below. Furthermore Ascorbic acid represents a physiological molecule. Sodium ascorbyl phosphate may after phosphatase-mediated hydrolysis become part of the physiological Ascorbic acid pool in the body.

In a dermal penetration study with the structural analogue L-ascorbic acid-2-phosphate magnesium salt (A2P) an absorption rate of 0.6926 nmole x cm2/h was determined. With a molecular weight of 278.39 g/mole a dermal penetration of 192.89 ng x cm2/h is caculated. For the dermal penetration assay 0.4 ml were applied on a surface area of 2 cm2. As a worst case assumption 1 mg/cm2 was used for calculation. In conclusion 0.019 %/h of L-ascorbic acid-2-phosphate magnesium salt (A2P) is resorbed via the skin. For a 8 h working day a dermal penetration of 0.16 % is calculated. For Sodium Ascorbyl Phosphate a dermal penetration of 1 % is assumed as a worst case assumption.

In the following the toxicokinetic behaviour of Ascorbic acid is summarised.

Absorption and tissue concentrations

Absorption studies have been carried out in rats and humans. In rats after an IP injection of 1.5-5.9 mg of 14C-labeled ascorbic acid, 19 - 29 % was converted to C02 and only 0.4 % was excreted as oxalic acid within 24 h. The average absorption of Ascorbic acid has been estimated to be 84 % in humans. Ascorbic acid is considered to enter in the physiological Ascorbic acid (vitamin C) pool. It was observed that increasing, oral intake from 1.5 to 12 g decreased the relative absorption of Ascorbic acid from about 50 % to only 16 % [summarised in 1].

The effect of ascorbic acid supplementation on CF1 mice fed ascorbic acid for approximately six months at dose levels of 1 %, 5 %, and 10 % of diet was investigated by analysis of tissue ascorbic acid concentration in the liver, kidney, stomach, small intestine, and large bowel. In the control animals, Ascorbic acid concentration was lowest in the liver (0.406 ±: 0.07 mg/g) and highest in the small bowel (0.754 ± 0.16 mg/g). Dietary intake of 5 % and 10 % ascorbic acid significantly elevated levels in the liver (0. 741 ± 0.13), and all doses of ascorbic acid significantly raised tissue concentrations in the kidney and colon [2].

L-Ascorbic acid was found in the adrenal and pituitary glands of rats at concentra-tions of 280 - 400 mg/100 g tissue and 100 – 130 mg/100 g tissue, and in the adrenal and pituitary glands of adult humans at concentrations of 30 – 40 mg/100 g tissue and 40 – 50mg/100 g tissue. Concentrations exceeding 10 – 15 mg/100 g tissue are found in the spleen, brain, liver, kidney, testes, eye lens, and white blood cells of both rats (strain unstated) and humans. In another study, rats and mice of unspecified strains were found to have L-ascorbic acid concentrations of 508 and 808 mg/100 g tissue in the adrenal glands and 349 and 1,052 mg/100 g in the ovaries. Concentrations of L-ascorbic acid in the pituitary gland were not reported. The body pool of ascorbic acid in rats (strain unspecified) has been calculated to be 10.7 mg/100 g body weight [summarized in 3].

Metabolism

Ascorbic acid undergoes biochemical degradation in the body and, when excess is administered, can be excreted unchanged. Ascorbic acid is oxidized to carbon dioxide in guinea pigs and rats and to oxalate in man. When 14C-ascorbic acid was administered by intraperitoneal injection to rats of an unspecified strain of doses of 44 or 51 mg, 0.57 % or 1.18 % of the dose was found as labeled oxalic acid in the urine. L-Xylonic acid, L-lyxonic acid, ascorbic acid-2-sulfate, and 2-methyl-L-ascorbic acid have been identified as metabolites of L-ascorbic acid in rats. The metabolism of ascorbic acid depends on several factors, including (among other things) the route of administration, dosage, and the nutritional status of the animal [summarized in 3].

Excretion

Ascorbic acid is excreted by glomerular filtration and active tubular reabsorption. The renal excretion threshold for vitamin C in humans is approximately 1.4 mg %. High doses of Ascorbic acid (4 g or more) increased the urinary excretion of oxalate. About 40 % of the urinary oxalate was derived from Ascorbic acid. It was observed that at daily intakes of 4 g of Ascorbic acid, the urinary oxalate level increased 10-fold, which may lead to the formation of kidney stones. However, in an evaluation of the safety of high vitamin C intakes, it was observed that even with large daily intakes the amount of oxalic acid formed was far too little to contribute significantly to oxalate formation [summarised in 1, 3].

References

[1] Madhavi, D.L. and Salunkhe, D.K. (1996):

Toxicological Aspects of Food Antioxidants, Food Science and Technology 71, 267-359

[2] Deschner, E.E., Alcock, N., Okamura, T., DeCosse, J.J. and Scherlock, P. (1983):

Tissue Concentrations and proliferative effects of massive doses of Ascorbic acid in the mouse, Nutrition and Cancer, Vol. 4, No. 4, 241-246

[3] US Department of Health and Human Services (1983):

NTP Technical Report on the carcinogenesis bioassay of L-Ascorbic acid (vitamin C) (CAS No. 50-81-7) in F344/N Rats and B6C3F1 mice (feed study).

[4] Mellert, W., Deckardt, K., Gembardt, C. and Hildebrand, B. (1998):

Sodium ascorbyl phosphate: Repeated dose oral toxicity study in Wistar rats, Administration in drinking water for 4 weeks and recovery period of 2 weeks, un-published BASF-Report