NDA 20-358

13

 

(A 14 day  rat study was also performed at doses of 100, 200, and 300 mg/kg/day; however, the drug used did not contain many of the impurities of interest and did not use a comparison group dosed with the original formulation.  Results were generally compatible with the 90 day study [salivation, increased liver weight] but no histopathological effects were seen, implying that more than 14 days’ treatment are needed to show such effects.

 

B was not teratogenic in a segment II study in Charles River rats (75, 150, 300 mg/kg), despite the production of some maternal toxicity.  lack of teratogenicity was also seen in the rat study (Long-Evans strain) performed under NDA 18-644.

 

In the Ames Test (plate incorporation method) B was borderline positive in strain TA 00 both in the absence and presence of metabolic activation.  A slight increase in revertants was seen in TA 1535 in the presence of activation, but this did not meet the stated criteria for a positive response.  When the preincubation method was used the pattern of responses was similar to the above although in no case were the stated criteria for a positive response was met.  Comparison groups using the “original” B were not used in these studies; however the responses seen here were strikingly similar to those seen in the study performed under NDA 18-644 in which 300 bit not 100 or 200 mg/kg caused an increase in chromosomal aberrations.

 

 

 

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