Hyaluronik asit

Acute Toxicity Studies No deaths were observed in an acute oral toxicity assay in which ICR mice were given > 1200 mg/kg Hyaluronic Acid.1 No other details were provided. Details on the acute oral toxicity studies summarized below can be found in Table 7. Several acute oral toxicity assays were performed using Sodium Hyaluronate in mice (at up to 15,000 mg/kg bw) and rats (at up to 5280 mg/kg bw).16 No signs of toxicity or deaths were reported in any of these assays. Short-Term and Subchronic Toxicity Studies No toxicity was observed in in a short-term inhalation toxicity assay performed in male Beagle dogs exposed to 10% Hyaluronic Acid formulations containing insulin. No other details were provided for this study. Details on the short-term and subchronic oral toxicity assays summarized below can be found in Table 8. No signs of toxicity were observed in short-term and subchronic oral toxicity assays of Sodium Hyaluronate.16 These assays include a 30-d study in which Wistar rats (10/sex/group) were given up to 1500 mg/kg bw Sodium Hyaluronate via feed, a 90-d assay in which Sprague-Dawley rats (5 - 10/sex/group) were given up to 48 mg/kg bw/d of Sodium Hyaluronate  Distributed for Comment Only -- Do Not Cite or Quote via gavage, a 90-d assay in which Wistar rats (10/sex/group) were given up to 1000 mg/kg bw/d Sodium Hyaluronate via feed, and a 90-d study using Wistar rats (12/sex/group) given up to 1333 mg/kg bw/d Sodium Hyaluronate in corn oil via gavage.

Details on the ocular irritation summarized below can be found in Table 11. No ocular irritation was observed in EpiOcularTM assays performed on 2 trade name mixtures containing 1% Hyaluronic Acid (tested neat), a trade name mixture containing 3% Hyaluronic Acid (tested neat), and a trade name mixture containing 0.5% Sodium Hyaluronate (tested neat).32-35 Test substances were considered to be non-irritating/slightly irritating in chorioallantoic membrane vascular assays (CAMVA) performed using Hydrolyzed Sodium Hyaluronate (FW < 1 kDa; concentration tested not reported) and Sodium Hyaluronate (tested neat).29,31 Similar results were observed in a bovine corneal opacity and permeability (BCOP) test performed using Sodium Hyaluronate (tested neat). In addition, a Bacillus- derived and Streptococcus-derived Hyaluronic Acid (up to 0.3%) was considered to be very well-tolerated when tested in the eyes of New Zealand white rabbits (3/group).41

Dermal Penetration Autoradiography was used to detect the dermal penetration of Hyaluronic Acid (in the form of [3H]hyaluronan) in SKh/1 hairless mice (4 animals/group; sex not stated; one group treated with radioactive gel; one group treated without  Distributed for Comment Only -- Do Not Cite or Quote radioactive gel).1 Mice were treated for either 3 or 12 total applications (12 h intervals). Twelve to 16 h after the last application, animals were examined. Radioactivity was found mainly in the dermis, from the outermost layer to the lymphatic and blood vessels. In a second experiment using 10 mice (strain and sex not reported; performed according to similar procedures), radioactivity was found in the same distribution within the dermis. In both assays, grains were found in the keratinized layer of the skin and hair follicles. In a dermal penetration assay performed in 11 Sprague-Dawley rats, Hyaluronic Acid (1.35 – 4.5 kDa) was applied dermally, twice daily, for 5 d. The Hyaluronic Acid penetrated to a maximum depth of 136 µm beneath the epidermis. In a different assay, radiolabeled Hyaluronic Acid was placed on the back of one Sprague-Dawley rat (sex not stated; singular dose). After a 4-h absorption period, the test substance was found to penetrate the rat skin to a maximum depth of approximately 800 µm. Autoradiography was used to detect the dermal penetration of [3H]Hyaluronic Acid gel (56.3 – 56.4 mg) in the forearm of one male subject (2 total applications 12 h apart; skin removed by biopsy 7 h after last treatment). The test substance was shown to disseminate through all layers of the skin. Hyaluronic Acid The dermal penetration of three Hyaluronic Acid solutions, with three different MW (20 - 50 kDa, 100 - 300 kDa, and 1000 - 1400 kDa), was evaluated via Raman microimaging.25 Test solutions contained 1% Hyaluronic Acid in distilled … [kırpıldı - bölüm toplam 4756 karakter]

No carcinogenicity data were found in the literature, and no unpublished data were submitted. OTHER RELEVANT STUDIES Immunogenicity Multiple injections of Hyaluronic Acid derived from human umbilical cords or streptococcal fermentation did not result in sensitization in immunogenicity studies performed in rabbits (administration of test substance via either subcutaneous or intramuscular route). In an antigenicity assay using injected streptococcal-derived Hyaluronic Acid in rabbits, precipitating antibodies were observed. A similar assay was performed using purified Hyaluronic Acid derived from rooster combs and  Distributed for Comment Only -- Do Not Cite or Quote human umbilical cords in rabbits. No formations of passive cutaneous anaphylaxis reactive antibodies were observed. Antibody response by rooster comb-derived Hyaluronic Acid caused an enhanced secondary antibody response to birch pollen, egg albumin (the protein in egg whites), and dog albumin in rats. Neither commercial Sodium Hyaluronate preparations nor a crude rooster comb Sodium Hyaluronate preparation elicited a Hyaluronic Acid-specific antibody response in rabbits. Cancer Cell Biology Mouse melanoma cell lines with high Hyaluronic Acid production had increased lung metastasis and lower survival than melanoma cell lines with lower Hyaluronic Acid production.1 Aneuploid human breast adenocarcinoma cells modified with antisense inhibition of hyaluronan synthase 2 expression produced more high MW Hyaluronic Acid. Injection of these cells into mice did not result in primary tumors. In other studies, well-differentiated tumors (e.g., salivary gland, stomach, colon) had intense Hyaluronic Acid-staining in the tumor cells, intratumoral and associated surrounding stroma. Poorly … [kırpıldı - bölüm toplam 4339 karakter]

Hyaluronic Acid was non-irritating in a single-stimulus skin test using Japanese rabbits and Hartley guinea pigs.1 In addition, no irritation was observed in a human closed skin patch test using Hyaluronic Acid produced via fermentation. No details were provided for either study. A skin prick test was performed in 9 subjects. The forearm of each subject was pricked with Sodium Hyaluronate (10 mg/ml), and evaluated 15 min, and 2, 6, and 24 h after pricking. No skin reactions were observed. Details on the dermal irritation and sensitization data summarized below can be found in Table 10. In vitro dermal irritation assays (EpiDermTM and reconstructed human epidermis assays) performed on two trade name mixtures containing 1% Hyaluronic Acid (tested neat), a trade name mixture containing 3% Hyaluronic Acid (tested neat), Hydrolyzed Sodium Hyaluronate (FW < 1 kDa; tested at 1%), a trade name mixture containing 0.5% Sodium Hyaluronate (tested neat), and Sodium Hyaluronate (concentration not reported) yielded negative results.29,31-35 No irritation was observed in human dermal irritation assays performed under occlusive conditions using Hydrolyzed Sodium Hyaluronate (several FW tested; 30 - 32 subjects; tested at up to 2%).31 No responses predicting sensitization were noted in a direct peptide reactivity assay (DPRA) performed on a trade name mixture containing 1% Hyaluronic Acid (tested at up to 25 mM), in a KeratinoSensTM assay performed on a trade name mixture containing 1% Hyaluronic Acid (up to 2 mM), and in a human cell line activation test (h-CLAT) performed on Sodium Hyaluronate (tested at 1 mg/ml).29,36,37 Similarly, no sensitization was observed in human repeat insult patch tests (HRIPTs) performed using a formula containing 0.2% Hyaluronic Acid (114 subjects; tested neat), a formula containing 0.2% Sodium Acetylated Hyaluronate (104 subjects; tested neat), Hydrolyzed … [kırpıldı - bölüm toplam 2567 karakter]