Is it safe to not power this USB to I2C chip when USB isn't plugged in?
Why not just do what the datasheet suggests as the Application example for an USB-to-I2C-converter? Which is having the USB-chip powered via USB and the pull-ups via the VCCIO which is driven by the USB-chips 3V3OUT? In that case the pull-ups would not be active when the USB-device is not powered and there should be no problem I think...