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Table 2 Safety tests of hyaluronan

From: Oral hyaluronan relieves knee pain: a review

Test procedures Subjects Route Results References
Randmized, double-blind, placebo-controlled trial Human Oral administration, 60 mg/day for 2 weeks No adverse event related to hyaluronan. [34]
Human Oral administration, 48 mg/day for 2 months No adverse event related to hyaluronan. [35]
Human Oral administration, 240 mg/day for 8 weeks No adverse event related to hyaluronan. [36]
Human Oral administration, 200 mg/day for 8 weeks No adverse event related to hyaluronan. [37]
Human Oral administration, 60 mg/day for 4 months No adverse event related to hyaluronan. [39]
Human Oral administration, 200 mg/day for 12 months No adverse event related to hyaluronan. [41]
Human Oral administration, 52 mg/day for 3 months No adverse event related to hyaluronan. [42]
Human Oral administration, 52 mg/day for 3 months No adverse event related to hyaluronan. [43]
Human Oral administration for 4 weeks (225 mg/day for first 2 weeks, 150 mg/day for last 2 weeks) No adverse event related to hyaluronan. [46]
single-dose toxicity study Mouse Oral administration LD50 (mg/kg) > 2400 [48]
Mouse Oral administration LD50 (mg/kg) > 500 [49]
Rat Oral administration LD50 (mg/kg) > 800 [48]
Rat Oral administration LD50 (mg/kg) > 200 [50]
Rabbit Oral administration LD50 (mg/kg) > 1000 [48]
Repeated-dose toxicity study Rat Subcutaneous administration for 13 weeks with 4 weeks recovery test NOAEL 50 mg/kg/day [51]
Beagle dog Subcutaneous administration for 13 weeks with 4 weeks recovery test NOAEL 10 mg/kg/day [52]
Rat Oral administration for 30 days NOAEL 1500 mg/kg/day [53]
Rat Oral administration for 90 days NOAEL 1333 mg/kg/day [54]
Rat Oral administration for 90 days NOAEL 1000 mg/kg/day [55]
Rat Oral administration 28 days NOAEL 3500 mg/kg/day [56]
Rat Intraperitoneal administration 90 days NOAEL 9 mg/kg/day [57]
Rat Intraperitoneal administration for 3 months NOAEL 60 mg/kg/day [58]
Rat Oral administration for 13 weeks NOAEL 12.5 mg/kg/day [59]
Rat Oral administration for 90 days with 28 days recovery test NOAEL 48 mg/kg/day [60]
Beagle dog Intra-articular administration for 6 months NOAEL 12 mg/kg/day [61]
Reproductive and developmental toxicity studies Rat Subcutaneous administration NOAEL 50 mg/kg/day [6264]
Rat Oral administration NOAEL 670 mg/kg/day [65]
Rat Subcutaneous administration NOAEL 50 mg/kg/day [6668]
Rabbit Subcutaneous administration NOAEL 50 mg/kg/day [69]
Mutagenicity test Reverse mutation test Bacteria(Ames test) 1000 μg/plate Negative [70]
Chromosomal aberration test Mammalian cultured cell 1.00 mg/mL Negative [71]
Mammalian cultured cell 1000 μg/plate Negative [72]
Micronucleus test Mouse 300 mg/kg Negative [73]
Mouse Intraperitoneal administration, 30 mg/kg Negative [74]
Antigenicity study Mouse, Rat Intraperitoneal administration, 100 μg/個体 Negative [75]
Guinea pig Negative
Rabbit Intramuscularl administration, 30 mg/kg Negative [76]
Influence on cancer cell Mouse, cell Oral administration, 200 mg/day No influence on cancer cell [77]