Chiliboy Ralepelle and Gurthro Steenkamp will return to South Africa after being injured in the Springboks' opening tour match against Leicester.
Ralepelle, who captained the side in Friday's shock 22-17 defeat at Welford Road, has to see a specialist over his injured foot.
Prop Steenkamp, meanwhile, has been suffering with a knee problem.
Hooker Adriaan Strauss and prop Wian du Preez, who both play for the Free State Cheetahs, have been called up.
Tight-head Jannie du Plessis is also doubtful with an injured hand, the South Africa Rugby Union (SARU) confirmed in a statement on their official website.
In addition, prop Tendai Mtawarira has been cleared to tour with South Africa, after the SARU and the sports ministry reached an agreement over the Zimbabwean-born player.
Mtawarira will now be available for selection for the Springboks' Test against France in Toulouse on Friday, 13 November.
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