Assessment of the Genotoxic Potential of Cizolirtine a Substance-P and Calcitonin Gene-Related Peptide Release Modulator

The analysis of the genotoxic potential of cizolirtine, a compound being developed as a drug for analgesia and for urinary incontinence, was carried out using a battery of in vitro and in vivo assays as recommended in the guidelines for medicinal products. Negative results were obtained in an Ames test (up to 5000 µg/plate), in a Mouse Lymphoma assay (up to 2000 µg/ml) and in a single dose mouse bone marrow micronucleus assay (up to 300 mg/kg). In a human lymphocyte chromosome aberration assay, a slight statistical increase in the frequency of cells with chromosome aberrations including gaps was reported for the concentrations of 200 and 1600 μg/ml at the 24-h sampling time. This minor increase in chromosome aberrations was considered of questionable biological relevance since it was moderate, was within the laboratory historical control values, did no show a dose-dependent effect and was not observed at similar concentrations in a repeat assay. Taking into considerations the results obtained in the different in vitro and in vivo assays and a weight-of-evidence analysis, it suggests that cizolirtine would not pose a genotoxic risk when administered to humans.

Toxicological assessment of β-galactosidase shows no adverse effects in vivo and in vitro

A safety assessment for β-galactosidase derived from Aspergillus oryzae (GODO-FAL) was performed. The test article was a concentrated, purified β-galactosidase diluted in glycerin and water with an activity of 10,000 U/mL. A series of genotoxicology tests including micronucleus assay, chromosome aberration assay, and reverse mutagenesis (Ames) assay confirmed that GODO-FAL was not clastogenic or mutagenic at any of the concentrations used, up to 2000 µg/mL for the chromosome aberration assay and 5000 mg per plate in the Ames assay. GODO-FAL was not toxic in acute, repeated oral toxicity, and sub-chronic toxicity assays in Sprague–Dawley rats at any dose used, up to 2000 mg/kg/day. Based on results from the subchronic toxicology assay, the no observed adverse effects level for GODO-FAL was at least 2000 mg/kg/day.

Toxicity Assessment of Biologically Degraded Product of Textile Dye Acid Red G

Azo dyes are of environmental concern due to their recalcitrant nature. Several azo dyes and their decolorized and degraded products exert toxic and mutagenic effects on the flora and fauna. The toxic properties of these azo dyes are due to nature and position of the substitution with respect to the aromatic rings and amino nitrogen atoms. Several studies have thus far been emphasized on biodegradation of azo dye pollutants, though role of their biodegraded product is rarely studied. Given a lack of this understanding, we have analyzed the effects of degraded products of a di-azo textile dye Acid Red G by newly isolated bacterial species, Pseudomonas aeruginosa PFK10 and Brevibacillus choshinensis PFK11. The genotoxicity and cytotoxicity of Acid Red G and their degraded products were tested on HeLa cell line and Human lymphocyte cell, respectively. The data of MTT assay has been shown that activity of degraded products of the Acid Red G were comparable to their parent dye. But chromosome aberration assay and sister chromatid exchange assay did not show any significant changes in chromosomes as compared to positive control mitomicine.

Safety assessment of nicotinamide riboside, a form of vitamin B3

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 present in trace amounts in some foods. Like niacin, it has been shown to be a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). The safety of Niagen™, a synthetic form of NR, was determined using a bacterial reverse mutagenesis assay (Ames), an in vitro chromosome aberration assay, an in vivo micronucleus assay, and acute, 14-day and 90-day rat toxicology studies. NR was not genotoxic. There was no mortality at an oral dose of 5000 mg/kg. Based on the results of a 14-day study, a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ovaries, and testes. The lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day.