Absolutely safe. Ram is ram. You can mix/match any DDR3 with any other DDR3 you care to, in anything upto a 16Gb stick.
That's not the issue, safety. The problems lie elsewhere. When mixing ram, there's no guarantee it will actually work. Ram is made from bits of silicon and they don't always get along. Ram will default to the lowest speeds, worst timings, highest voltages of all the combined ram, so mixing 1333MHz cl9 1.65v with 1600MHz cl11 1.5v means all the ram combined will run at 1333MHz, cl11 1.65v.
On top of that is size. For true dual channel you need same size. Using oddball sizes means Flex mode. What you get is 4Gb of 1333 will run dual channel with the first 4Gb of the 1600, the remaining 4Gb of the 1600 will run single channel. If the programs on the pc are running 3-5Gb, which is normal, you'll get flip-flop as the pc switches some ram usage to single channel.
Safe? Absolutely. Won't hurt pc working at all.
Wise? Not really, you'll suffer some performance issues and there's always the possibility that the mix simply won't function as desired.