England coach Steve Borthwick has been forced into a rethink at scrumhalf for his opening Six Nations game away to Ireland after Jack van Poortvliet and Alex Mitchell picked up injuries over the weekend and were replaced by Ben Spencer and Raffi Quirke.
Jamie George, who was last week replaced as captain by Maro Itoje, Alex Coles and Alex Dombrandt were also ruled out and replaced by Curtis Langdon, Arthur Clark and Northampton's 20-year-old flanker Henry Pollock.
Mitchell, who missed the November internationals, had been expected to go straight back into the team for the tough February 1 opener in Dublin. The RFU said on Tuesday he will travel with the squad to their training camp in Girona to continue his rehabilitation.
Borthwick will give more details of the changes at the Six Nations launch in Rome later on Tuesday.