Prop Lourens Adriaanse and flanker Nizaam Carr have replaced Jannie du Plessis and Jaco Kriel in the South African squad for the upcoming autumn internationals.
Kriel sustained a grade two tear of his left MCL at the weekend while playing club rugby in Japan.
He has returned to Johannesburg for treatment and will be out of action for approximately four weeks, which rules him out of the November Tests against the Barbarians, England, Italy and Wales.
The injury is a setback for coach Allister Coetzee, who is already without the services of regular number six Francois Louw, who has also been ruled out for the rest of the year.
It leaves Coetzee with few options at openside flanker since Marcell Coetzee, who has moved to Irish club Ulster, is still recovering from a serious knee injury.
Experienced Montpellier prop Du Plessis has also withdrawn from the Springboks squad because his wife is due to give birth to the couple's third child in early November.
"Jannie and I had a good conversation on Wednesday evening and he still has a burning desire to be part of the Springboks. However, due to his current personal circumstances, he unfortunately had to withdraw from the squad," said Allister Coetzee.
"Jannie has a wealth of experience, he still has a lot to offer and he stays part of our plans. I want to wish him and his wife well as they are looking forward to welcome a third addition to their family."
The Springboks are scheduled to have their final training session on home soil on Friday morning before flying out to London in the early evening.
Revised South Africa Test squad
Forwards (18): Lourens Adriaanse, Willem Alberts, Nizaam Carr, Eben Etzebeth, Lood de Jager, Steven Kitshoff, Vincent Koch, Malcolm Marx, Bongi Mbonambi, Oupa Mohoje, Franco Mostert, Tendai Mtawarira, Trevor Nyakane, Jean-Luc du Preez, Roelof Smit, Adriaan Strauss (capt), Pieter-Steph du Toit, Warren Whiteley
Backs (15): Damian de Allende, Ruan Combrinck, Faf de Klerk, Johan Goosen, Bryan Habana, Elton Jantjies, Jesse Kriel, Patrick Lambie, Lionel Mapoe, Rudy Paige, Sergeal Petersen, JP Pietersen, Willie le Roux, Francois Venter, Piet van Zyl