Sodium ascorbate

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

other: Scientific evaluation

Title:

Scientific Opinion on the re-evaluation of ascorbic acid (E 300), sodium ascorbate (E 301) and calcium ascorbate (E 302) as food additives.

Author:

EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food)

Year:

2015

Bibliographic source:

EFSA Journal 2015;13(5):4087, 124 pp

Materials and methods

Objective of study:

absorption

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Secondary source information from several studies without detailed methods.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Ascorbic acid

EC Number:

200-066-2

EC Name:

Ascorbic acid

Cas Number:

50-81-7

Molecular formula:

C6H8O6

IUPAC Name:

5-(1,2-dihydroxyethyl)-3,4-dihydroxyfuran-2(5H)-one (non-preferred name)

Test material form:

solid

Details on test material:

- Impurities (identity and concentrations): not specified
- Isomers composition: > 99% L-Ascorbic Acid

Specific details on test material used for the study:

CAS number: 50-81-7

Radiolabelling:

no

Test animals

Species:

other: dog, among other unspecified species

Sex:

not specified

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

not specified

Control animals:

not specified

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Ascorbic acid is rapidly absorbed from the intestine by a sodium-dependent active transport process. The absorption efficiency is up to 98% at low doses and onöy 2% are excreted into faeces. The tranporter is saturable, the absorption efficiency therefore gradually decreases at higher intakes to 80-90% at up to 180 mg, 75 % at 1g and 16% at 12g.
Reference: Hornig and Moser, 1981 (and several other publications)

Details on distribution in tissues:

Ascorbic acid is readily oxidised to dehydroascorbic acid which can be reduced back to ascorbic acid or hydrolysed (irreversibly) to diketogulonic acid. The latter is partly excreted with urine and partly oxidised to mainly oxalic acid and threonic acid (and to a lesser extent to xylose, xylonic acid and lyxonic acid). Oxidation to carbon dioxide is not a major route but may occur at high doses, possibly as a result of metabolism of unabsorbed ascorbate by the intestinal microflora. To some extent, ascorbic acid may also form a conjugate with sulphate which is excreted in the urine as is unchanged ascorbic acid. The percentage that is excreted depends on the dose. Only 3% of a 60 mg dose is excreted in the faeces, while the majority is excreted in the faeces at very high doses, e.g. 1 g or more. At total daily intakes above 80-100 mg, most of the ascorbic acid above this dose range is excreted unchanged in the urine, indicating that tissues reserves are saturated.
References: Blanchard et al., 1997; Kallner et al., 1979; 1985

Details on excretion:

cf. sections above

Any other information on results incl. tables

The pharmacokinetics of ascorbic acid and calcium ascorbate were investigated in 20 dogs. The animals received single oral doses at two dose levels, 15 and 50 mg/kg bw. A rapid increase of the ascorbic acid plasma level was seen. The obtained Cmax and area under the curve values increased in a non-linear fashion with the increased dose.

There was no significant difference in pharmacokinetic parameters between ascorbic acid and calcium ascorbate. (Wang et al., 2001).

The EFSA ANS Panel considered that sodium and calcium ascorbate are fully dissociated in the stomach, and that the bioavailability would be expected to be similar to that of ascorbic acid in the gastrointestinal tract (EFSA ANS Panel, 2015).

Applicant's summary and conclusion

Conclusions:

The absorption of ascorbic acid is saturable. It is readily absorbed from the GI tract up to daily doses of 80-100 mg. Excess ascorbic acid is excreted in the urine and with the faeces. Metabolites of the absorbed ascorbic acid are mainly excreted in the urine.

Pharmacokinetic studies indicate that there is no differences between ascorbic acid and calcium ascorbate. It is considered that this holds also true for any other dissociable form of ascorbate including sodium ascorbate. Hence, results from studies on ascorbic acid may be adopted for sodium ascorbate.

Executive summary:

The scientific evaluation of ascorbic acid considers numerous studies on the absorption, distribution, metabolism and excretion of ascorbic acid and some of its dissociable salts. No pharmacokinetic difference was seen between ascorbic acid and calcium ascorbate, and it is expected, that this finding can also be adopted for other ascorbates including sodium ascorbate, thus allowing read across between ascorbic acid and sodium ascorbate.

Ascorbic acid is readily absorbed from the GI tract, distributed and metabolised. Metabolites are mainly excreted in the urine. Absorption is saturated at doses of more than 80-100 mg/day, i.e. excess ascorbic acid is excreted changed in the faeces and in urine. Hence, the plasma levels (Cmax) and the area under the curve (AUC) increase in a sub-linear fashion with increasing doses of ascorbic acid.

Ingested ascorbic acid and ascorbate salts are considered to be fully dissociated at the low pH in the stomach and it is expected that the bioavailability from the gut is similar (EFSA ANS Panel, 2015)

This consideration is supported by the experimental data outlined above. On this basis, results obtained after oral dosing with ascorbic acid or sodium ascorbate can be used for mutual read across.