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Bodies littered the scene and a towering plume of smoke rose from the area, which houses foreign embassies, after the blast blew out the windows in several missions and residences hundreds of metres away.
Witnesses described dozens of cars choking the roads as wounded survivors and panicked schoolgirls sought safety, with men and women struggling to get through security checkpoints to search for loved ones.
It was not immediately clear what the target was. But the attack underscores spiralling insecurity in Afghanistan, where a military beset by soaring casualties and desertions is struggling to beat back the insurgents. Over a third of the country is outside government control.
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Health ministry spokesman Waheed Majroh said at least 49 people had been killed and 320 wounded, with the figures confirmed by a second health official and the government media office.
Authorities warned the toll could yet rise. “They are still bringing bodies and wounded people to hospitals,” senior health ministry spokesman Ismael Kawoosi told AFP.
The interior ministry was calling on Kabul residents to donate blood, saying hospitals were in “dire need”.
There was no immediate claim of responsibility, but the attack came as the resurgent Taliban step up their annual “spring offensive”.
The Islamic State group has also claimed responsibility for several recent bombings in the Afghan capital, including a powerful blast targeting an armoured NATO convoy that killed at least eight people and wounded 28 on May 3.
Najib Danish, an interior ministry spokesman, said initial findings showed it had been a truck bomb.
Manpreet Vohra, India’s envoy to Afghanistan, told the Times Now television channel the bomb went off around 100 metres from India’s embassy, one of several in the area.
“We are all safe, all our staff, all our personnel are safe. However, the blast was very large and nearby buildings including our own building have considerable damage in terms of broken glass and shattered windows and blown doors etc,” he said.
Indian Prime Minister Narendra Modi tweeted: “We strongly condemn the terrorist blast in Kabul. Our thoughts are with the families of the deceased & prayers with the injured.”
The explosion also shattered windows at the Japanese embassy. “Two Japanese embassy staffers were mildly injured, suffering cuts,” a foreign ministry official in Tokyo told AFP.
France also reported damage to its own embassy and the German one.
Pentagon chief Jim Mattis has warned of “another tough year” for both foreign troops and local forces in Afghanistan.
Afghan troops are backed by US and NATO forces, and the Pentagon has reportedly asked the White House to send thousands more troops to the country to break the deadlock in the fight against the Taliban.
US troops in Afghanistan number about 8,400 today, and there are another 5,000 from NATO allies. They mainly serve in an advisory capacity — a far cry from the US presence of more than 100,000 six years ago.
The blast was the latest in a long line of attacks in Kabul. The province surrounding the capital had the highest number of casualties in the first three months of 2017 due to multiple attacks in the city, with civilians bearing the brunt of the violence.