Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is a white crystalline powder or granule. It is an organic monoconstituent with purity of 99% - 100% with 1 minor impurity (< 1% ).
A full ADME toxicokinetic study in the rat is not available. An in vivo toxicokinetic study on metabolism/excretion in animals of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is available (Final Report on the Safety Assessment of Ascorbyl Palmitate, Ascorbyl Dipalmitate, Ascorbyl Stearate, Erythorbic Acid, and sodium Erythorbate, Andersen, 1999). The toxicokinetic analysis is based on data from physicochemical data and in vivo animal models. In vivo studies covering the oral (acute oral toxicity study and combined repeated dose toxicity/carcinogenicity studies) and dermal (skin irritation and skin sensitisation) routes are available. There are no studies covering the inhalational route available. Further details on endpoints are available in the IUCLID 5 registration dossier.
Based on the physicochemical properties and information in the dossier, 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is expected to be absorbed after oral and inhalation exposure. Dermal absorption is likely to be negligible. 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone may be distributed and converted to water soluble metabolites to facilitate excretion. The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information

1. Physicochemical properties

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone in the body.

Absorption - oral

The molecular weight (199.12 g/mol) and water solubility of 146 g/L at 20°C are favorable for oral absorption of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone. The log P of -3.29 (estimated) suggests that 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is considerably hydrophilic and is not in the favourable range for passive diffusion (log P: -1 to 4) or absorption via the lymphatic system (log >5). As 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is very hydrophilic and the molecular weight is <200 g/mol, it may pass through aqueous pore, be carried through the epithelial barrier by the bulk passage of water, or an active transport mechanism may be involved.

Absorption – dermal

The molecular weight of 199.12 g/mol is above the range for favorable dermal absorption (<100 g/mol). The water solubility of 149 g/L at 20°C and poor lipophilicity (log P of -3.29, estimated) indicate that 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is likely to be too hydrophilic to cross the stratum corneum, therefore dermal absorption is likely to be low.

Absorption – inhalation

The particle size distribution report for 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone indicates a range of is 4.365 μm - 1096.478 μm (d(0.1): 194.798 μm d(0.5): 383.138 μm d(0.9): 649.050 μm). The % of particles available in the inhalable fractions of air (<100 μm) is likely to be negligible. Based on the molecular weight (199.12 g/mol), water solubility (149 g/L) and particle size, 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone may readily diffuse/dissolve into the mucus lining the respiratory tract. As it is very hydrophilic (log P: -3.29) it may be absorbed through aqueous pores (molecular weight <200) or be retained in the mucus and transported out of the respiratory tract. So there is potential for absorption via the inhalational route.

Distribution/Metabolism

The molecular weight (199.12 g/mol) and water solubility (149 g/L at 20°C) of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone are favourable for wide distribution but the very low log P (-3.29, estimated) indicates it is not likely to accumulate in fat during intermittent exposure.

Excretion

Based upon the molecular weight of 199.12 g/mol and water solubility of 149 g/L at 20°C, it is likely that 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is excreted mainly in the urine.

2. Information from other studies in the dossier

Absorption - oral

In the acute oral gavage toxicity study (LD 50: >5000 mg/kg bw), gastrointestinal disturbances (soft stools, diarrhoea up to 24 hrs) were noted. In the combined repeated dose/carcinogenicity toxicity study (mouse 10 week study), the maximum tolerated dose (MTD) of 2,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone in drinking water for males was 2.5% and 5% for females. Body weight changes were noted in both sexes and histopathological changes were noted in the spleen, liver and kidney in males at doses above the MTD. In the main 96 week mouse study, dose-dependent reductions in the heart and brain weights were observed in male mice and the weights of the heart, lungs, kidneys, and brain of female mice were significantly different between the high dose and control groups (non-tumour bearing mice). In the oral gavage developmental toxicity studies (rat NOAEL 900 mg/kg bw/day; mouse NOAEL 1030 mg/kg bw/day), no treatment-related effects were noted. These studies indicate that there is systemic absorption after oral administration. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, an oral absorption rate of 50% is accepted.

Absorption - dermal

The in vivo skin irritation study in rabbits showed that 3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone was not irritating to the skin. The LLNA skin sensitisation study in mice indicated that ,3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone is not sensitizing. The log P (-3.29, estimated) indicate that FAS is not likely to be sufficiently lipophilic to cross the stratum corneum and negligible systemic absorption is expected. The available in vivo dermal toxicity data together with the physicochemical data indicates that any significant dermal absorption is unlikely. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption-Inhalation

There are no studies covering the inhalational route available.For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, as no inhalational toxicity data is available for the substance.

Distribution/Metabolism/Excretion

In a dietary study, 3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone was administered to Male F344 rats (five per group) at dose levels of 5% for 22 weeks. The rats eliminated totals of 203.3 ± 33.2 mg/100 mL erythorbic acid and 9.0 ± 5.1 mg/100 mL dehydroerythorbic acid during the study. Ascorbic acid and dehydroascorbic acid were not detected. Urine pH was 6.98 ±0.31, which was significantly different from that of rats given basal diet alone (6.31 ± 0.18; p < 0.05). Urine osmolarity also differed significantly from controls; osmolarity was 1378 ± 277 mOsmol/kg H20 in rats given Sodium Erythorbate and 1756 ± 200 mOsmol/kg H20 in rats of the control group. Crystals were detected in urine of rats given basal diet and Sodium Erythorbate or basal diet alone. This study indicated that erythorbic acid is the major metabolite and dehydroerythorbic acid is the minor metabolite of 3-didehydro-3-O-sodio-D-erythro-hexono-1,4-lactone and it is expected to be excreted in the urine.