Salcaprozate sodium (SNAC) (sodium 8-((2-hydroxybenzoyl)amino) octanoate, CAS RN 203787-91-1) is classified as an oral absorption promoter. Although several clinical investigations have explored the potential therapeutic applications of Salcaprozate sodium (SNAC) as a delivery agent for oral forms of heparin and insulin, limited information about the nonclinical safety of Salcaprozate sodium (SNAC) itself was found in the published scientific literature. In a published review article on the development of an oral heparin formulation, the results of Salcaprozate sodium (SNAC) toxicological studies are given, but the item provides no details regarding their conduct.
The present report summarizes the findings of a study that examined the effects of Salcaprozate sodium (SNAC) on the gestation, parturition, lactation, maternal behavior, and offspring development of rats. In that study, Salcaprozate sodium (SNAC) was administered to pregnant rats at 0, 500, 750, and 1000 mg/kg/d with 5000 USP units of heparin sodium/d. The study, sponsored by Emisphere Technologies, Inc (Cedar Knolls, New Jersey), involved extensive evaluations and conformed to International Conference on Harmonization (ICH) Harmonized Tripartite Guideline stages C (implantation) through F (lactation and weaning) of the reproductive process. To detect any potential delayed adverse effects resulting from prenatal and perinatal Salcaprozate sodium (SNAC) exposure, observations weremade until F1 generation rats reached sexual maturity and F1 females became pregnant. Only the findings from groups treated with SNAC alone or the vehicle (deionized water) are included in the present report because the presence of heparin in other groups might be confounding.
Test Substance, Dose Selection, and Dosing
Salcaprozate sodium (SNAC) (lot no. E414-47S [EM 0074], 93.2% purity) was stored at room temperature with desiccant. Information concerning the identity, composition, strength and activity of Salcaprozate sodium (SNAC) was established before initiation of this study. Stability of the prepared formulation at concentrations bracketing the range to be used in this study was established during the course of a dosage range study in rats . Dosing solutions of Salcaprozate sodium (SNAC) were considered to be within an acceptable range if they were between 90.0% and 110.0% of the stated concentration.
An oral dose of 1000 mg/kg body weight/d is used in the Organization for Economic Cooperation and Development (OECD) and European Union (EU) guidelines as a default maximum dose in limit tests for studies on reproductive toxicity.
Animals received the vehicle (deionized water) or Salcaprozate sodium (SNAC) at 1000 mg per kg of body weight per day(1000 mg/kg/d) by oral gavage. The dosage was adjusted daily, based on the most recently obtained rat body weights. Dosing solutions were prepared at least once weekly, and Salcaprozate sodium (SNAC) was considered 100% active for the purpose of dose calculations. Prepared formulations were stored refrigerated (approximately 35-46oF). F0 generation females received the vehicle or Salcaprozate sodium (SNAC) once daily from day 7 of gestation (DG 7) through day 20 of lactation (DL 20). F1 pups weaned on DL 21 were selected for continued evaluation. F1 generation animals did not receive SNAC directly but potentially would have been exposed to SNAC in utero and/or via maternal milk during lactation.
Clinical signs noted in SNAC-treated (F0) dams during late gestation and early lactation consisted of excess salivation (in 13/24 dams vs 1/24 dams in control) and red perivaginal substance (in 9/24 dams vs 1/24 dams in control). As shown in Table 1, dam body weights were slightly lower than control throughout gestation, reaching statistical significance (P≤.01) only on gestation day (DG) 20. However, maternal body weights were only a maximum of –3.8% of mean control values on DG 20. Body weights were also slightly lower during lactation, but the differences were not statistically significant (Table 2). SNAC-treated dams had significantly (P ≤.01) smaller body weight gains (days 0-20) than vehicle control dams but only during gestation. Some minor reductions in feed consumption were also observed during gestation (–5.8% of control values from DG 7-20) but were not overall statistically significant. Dosages of Salcaprozate sodium (SNAC) as high as 1000mg/kg/d did not affect maternal feed consumption values during lactation (data not shown).
- Gary I, International Journal of Toxicology Volume 28 Number 4 July/August 2009 266-277