Alex Cuthbert has joined Dan Biggar and Liam Williams in withdrawing from Wales to face South Africa in Cardiff on Saturday (3.15pm BST).
Tom Rogers will replace Cuthbert, who has a tight calf, in a third change from the squad originally named for Wales’ final World Cup warm-up game.
Sam Costelow replaces fly-half Biggar, who is suffering from a back spasm.
Cai Evans earns his first cap after replacing full-back Williams, who has a tight hamstring.
Louis Rees-Zammit is named as replacement.
Cuthbert had also missed training camps in Switzerland and the first two preparation matches for Turkey and Wales through injury.
Wales’ starting back line has just 39 caps left between them, with scrum-half Kieran Hardy having 17.
Head coach Warren Gatland will name his 33-man squad for the World Cup on Monday, August 21.
Wales stressed Biggar and Williams’ withdrawals were a precaution and they are not World Cup doubts.
“They’re not serious at all,” Gatland said. “If it was a World Cup semi-final, Dan Biggar would have been fine for the weekend.
“We are just taking a precautionary measure. There is no need for us to take a risk with him.
“Both [Williams and Biggar]if pushed hard, could play on Saturday, but decision made [that] there is no point in taking a risk at this point.
“It’s about dealing with things that are going to be thrown at you. He uses a bit of adversity as a positive.”
Hooker Dewi Lake is in contention to be fit for the World Cup opener against Fiji in Bordeaux on September 10 with back line Taine Plumtree, hooker Ryan Elias and lock Dafydd Jenkins also targeting that fixture .
Cuthbert, number eight Taulupe Faletau (calf) and fly-half Gareth Anscombe (thumb) are the only players in the 48-man squad who have not been able to play in any of the three warm-up games.
Dragons hooker Bradley Roberts was called up to train with Wales to provide cover amid injuries to Lake and Elias, who suffered a hamstring injury in the 20-9 Premier League win. opening World Cup warm-up against England in Cardiff in early August.
Roberts Dragons hooker Elliot Dee will start against South Africa with Sam Parry on the substitutes’ bench.
Gatland said it was a balancing act on how many players he could select with fitness issues.
“In the past we’ve gone to World Cups with players with issues that are going to take two or three weeks to come through,” Gatland said.
“That may be the case, but it just depends on what kind of risk you are potentially taking.
“There’s maybe one or two we can take with concern, that’s probably the number you’re talking about.
“The important thing is when you can get back to training. If you look at the draw you have to go all out for the first game and then looking at Portugal with a six-day deadline there will be changes.
“Then you have eight days for Australia where you will be a strong team again and then a turnaround of 13 days where hopefully everyone will have a chance to recover from the knocks and bruises before playing. against Georgia.
“There’s less pressure in this tournament than there has been in the past where you’ve had four-day deadlines when it’s had a pretty big impact on the team.
“It’s a discussion that we will have in terms of risk and how much we can carry.”
Gatland has insisted Dragons flanker Taine Basham is fit to play against South Africa after recovering from a high tackle from England captain Owen Farrell.
Basham, 23, failed his head injury assessment (HIA) the same day, but Gatland had written in his diary column that the process had been flawed because there was a television on in the same room.
The WRU claim Basham is fit to feature on the bench as no concussion has been confirmed following the completion of the three stages of World Rugby’s HIA protocol.
“He had a full week with us starting Monday, he passed his HIA 2 and 3, so no problem at all,” Gatland said.
“He felt good after the game. He felt good when he was on the pitch. He was an independent doctor who took a look and said he wanted him to have an HIA.”
An independent judicial panel has overturned Farrell’s dismissal against Wales, clearing him to play a key role for England at the upcoming World Cup.
World Rugby has now appealed the decision and another hearing is to be held.
Gatland would not be drawn to controversy Farrell after initially criticizing the England fly-half’s tackling technique in his newspaper column.
“I’ve been upfront that he needs to improve his technique a bit,” Gatland said.
“It’s something we talk about with the players: if you don’t bend at the hips, you put yourself in a situation where you can potentially receive a yellow card or a red card.
“I’d like to think all coaches talk about tackling technique and doing those things right. And if you don’t do those things right, then you can potentially put yourself in a position where you can be carded.
“Everyone wants clarity and certainty on all aspects of the game.”
The Wales team will face South Africa: C Evans; Rogers, Grady, J. Williams, Dyer; Costelow, Hardy; Domachowski, Dee, Assiratti, Carter, Rowlands, Lydiate, Morgan (captain), Wainwright.
Subs: Parry, N Smith, H Thomas, Teddy Williams, Basham, Tomos Williams, Llewellyn, Rees-Zammit.
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