DAVID Cameron has warned voters that leaving the EU could lead to the "disintegration" of the United Kingdom in his strongest use of the Union card to date during the in-out referendum campaign.

Noting how the UK was a voluntary union of four nations, the Prime Minister urged voters to go to the ballot box with their "eyes open".

First Minister Nicola Sturgeon has said there would be an ''almost certain'' drive for another independence referendum north of the border if Scotland voted to stay in the EU but England voted to leave.

All of Scotland's major parties are firmly in the Remain camp and support among voters wanting to stay in outnumbers Leave by around two to one.

During a speech at the British Museum setting out the case for Britain remaining part of the Brussels bloc, Mr Cameron warned that Brexit could fuel a fresh push for Scottish independence.

"Let me just say this about Scotland; you don't renew your country by taking a decision that could ultimately lead to its disintegration. So, as we weigh up this decision, let us do so with our eyes open," declared the PM.

Last week under cross-examination by MPs, Mr Cameron played the Union card.

After stressing the June 23 vote would be a decision for the UK as a whole, he then alluded to the possibility of a second independence poll by stressing: "I would argue to anyone in the United Kingdom who cares as passionately as I do about keeping the United Kingdom together that the safe and sensible choice is to vote to stay in a reformed European Union."

Senior politicians from ex-premiers Sir John Major and Tony Blair to former Deputy Prime Minister Nick Clegg and Labour’s Alan Johnson, the former Home Secretary leading the Labour In campaign, have all warned that a UK vote to leave the EU while Scotland voted to stay would lead to a second independence referendum and the possibility of the break-up of Britain.

In the wake of last week’s Holyrood results Ruth Davidson, the Scottish Conservative leader who now heads the main opposition in the Scottish Parliament, claimed Scotland had passed "peak Nat" and that no second independence referendum could be staged in the next five years; the latter point was echoed at the weekend by Michael Gove, the Justice Secretary.

Many of Nicola Sturgeon’s opponents believe the SNP manifesto does not give her the right to call a second poll on independence but the First Minister has continually suggested that if Scotland were dragged out of the EU against its will, then this would provide the material change necessary to call another referendum; equally, such a circumstance would be met if there were a consistent and majority demand from the Scottish public for a second poll.