NDA 20-358

8

 

SEGMENT II REPRODUCTION IN RATS:

 

A)     Dosage

 

30 F at 0, 75 (LD), 150 (MD), or 300 (HD) mg/kg/day of “degraded” drug (i.e., containing impurities), or 300 mg/kg/day of undegraded drug (this group hereafter referred to as HD*), days 6-15 of gestation, by gavage.

 

Dams sacrificed day 20 of gestation.  Live fetuses examined externally; 1/2 examined for visceral effects using a fresh tissue dissection method (+ Wilson sectioning of head); these + remaining fetuses examined for skeletal effects with alcian blue/alizarin red S.

 

Strain: CD BR Charles River

 

B)      Results

 

1)       Observed signs

 

a)       Hyperactivity at all doses, D-R: similar incidence at HD and HD*; not seen after day 9 gestation.

 

b)       “Rooting in bedding” (Said to be consistent with “taste aversion:) seen at all doses, generally D-R; similar incidence at HD and HD*.

 

2)       Mortality

 

None

 

3)       Bodyweight

 

Decreased gain/slight loss at all doses, D-R days 6-9 gestation; similar effect at HD and HD*.  At the end of the dosing period (day 16 of gestation) weight was 97%, 97%, 94% and 93% of control at LD, MD, HD, and HD*, resp.  Treated groups tended to gain more than controls day 18-20 of gestation although on day 20 weights were still slightly below control

 

4)       Food consumption

 

Decreased at all doses, D-R, esp. during days 6-9 of gestation.  No difference between HD and HD*.  Consumption tended to be slightly increased above controls days 16-20 of gestation.

 

5)       Reproductive data

 

Pregnancy rate was slightly decreased at HD and HD* (approx. 85% vs 97% in control).

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