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Sprague Dawley (JCL:SD) rats were administered D-glucono-1,5-lactone (GDL) by oral gavage at daily doses of 0 (vehicle control), 250, 500, 1000, 2000, or 4000 mg/kg body weight for 6 months in a key, repeat-dose toxicity study.  This non-GLP study was equivalent to OECD Test Guideline 408. A No-Observed-Adverse-Effect Level (NOAEL) was not identified by the authors and one could not be determined as pathological effects in the stomach were observed in all dose-groups.  However, these effects were considered not to be relevant to humans.  Based on a review of the data, the Lowest-Observed-Adverse Effect Level (LOAEL) was determined to be 250 mg/kg body weight in rats. 
No supporting oral studies were located and no inhalation or dermal repeat-dose toxicity studies have been conducted.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
250 mg/kg bw/day

Additional information

In a 6-month repeat-dose toxicity study, Sprague-Dawley(JCL:SD) rats were administered GDL by oral gavage at daily doses of 0 (vehicle control), 250, 500, 1000, 2000, or 4000 mg/kg body weight (Hukuhara et al., 1978). This non-GLP study was equivalent to OECD test guideline 408. Oral administration of GDL for 6 months at doses up to 4000 mg/kg body weight had no adverse effects on mortality, body weights or body weight gains, food consumption, or urinalysis. Significant changes in haematology and organ weights were observed but were sporadic, not dose-dependent, and occurred in one sex only, and therefore, were not considered compound related. Significant clinical chemistry changes were observed in males and females. Increased albumin levels and decreased total cholesterol levels were observed in males in the 1000, 2000, and 4000 mg/kg body weight/day groups. Significantly decreased blood urea nitrogen levels were noted in males dosed at 4000 mg/kg body weight/day. All changes in males appeared to be dose-dependent. In females, significant changes observed were sporadic and not dose-dependent. Increased blood urea nitrogen levels in the 250 mg/kg body weight/day group, decreased alanine aminotransferase activity levels in the 1000 mg/kg body weight/day group, decreased calcium levels in the 4000 mg/kg body weight/day group, and increased alkaline phosphatase activity levels in the 4000 mg/kg body weight/day group were observed. Histopathological changes included a dose-dependent increase in frequency and severity of hypertrophy of stratified squamous epithelium in the anterior stomach, particularly the transitional area continuous with the pyloric stomach, which was observed in all groups dosed with GDL. These changes appear to have been observed in the rat forestomach, particularly the limiting ridge, which are structures unique to rodents. Thus, the effects observed in the rat stomach upon exposure to GDL are not relevant to humans. In 3 male rats and 1 female rat at 4000 mg/kg body weight/day and 1 female rat at 500 mg/kg body weight/day, inflammatory cellular infiltration under mucous membrane was also observed. The degree of infiltration was not considered to be severe, but was considered to be compound-related. A NOAEL was not determined by the authors and one could not be determined based on the results of the study. However, based on the review of the data, the LOAEL was determined to be 250 mg/kg body weight in rats.

D-glucono-δ-lactone is a cyclic ester of gluconic acid which, in aqueous solution, forms an equilibrium mixture of the lactone and gluconic acid. Gluconic acid is a somewhat weak carboxylic acid with a dissociation constant of pKa = 3.6. The dissociation of an acid into a proton and an anion is an equilibrium, the reverse of which is the re-association of that same anion with a proton to reform the original acid. The pKa of 3.6 means that, when the ambient pH = 3.6, half the gluconic acid molecules will exist in the form of the uncharged acid, and half as the anion. At pH < 3.6, the undissociated form will predominate, and pH > 3.6 the anion will predominate. Sodium gluconate and potassium gluconate are both 1:1 salts of gluconic acid, which will each dissolve in water to generate separate sodium or potassium cations and gluconate anions. Sodium and potassium are both strong bases, and are therefore expected to remain ionized at essentially any pH, but the gluconate anions deriving from the salts will be subject to the same equilibrium as those deriving from the free acid. To be in equilibrium, both the forward and the backward reaction must possess the same pKa value, so the gluconate anion is predicted to posses the same pKa of 3.6 as the free acid. In this way, gluconic acid in aqueous solution is in equilibrium with its cyclic esters and its anion, according to the pH of the system, and in any system with sufficient buffering capacity, the effects of introducing equimolar amounts of gluconic acid, D-glucono-δ-lactone, sodium gluconate or potassium gluconate would be indistinguishable. Hence these four substances are considered to be appropriate surrogates for each other in sufficiently buffered aqueous systems, such as environmental waters, flora and fauna.

Justification for classification or non-classification