The MV Cape Ray, which is outfitted with portable hydrolysis machinery, launched the effort after having loaded on board 600 metric tonnes of chemical agents at an Italian port on July 2, spokesman Colonel Steven Warren told reporters.
"We expect neutralization to take approximately 60 days," Warren said.
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After breaking down the lethal chemicals to a sludge equivalent to industrial waste, the byproducts will be transported to Finland and Germany for final disposal, he said.
Syria handed over sulfur mustard and a precursor to make Sarin gas under the terms of a UN-backed and US-Russia brokered agreement to head off Western air strikes against the regime last year.
The deal came after global outrage over chemical attacks by Bashar al-Assad's regime in the suburbs of Damascus on August 23 last year, which may have killed as many as 1,400 people.
The ground-breaking arrangement to neutralize the chemicals at sea was agreed because no country was ready to host an operation to destroy the agents.
A Danish ship initially picked up the chemical agents and delivered them to the southern Italian port of Gioia Tauro, amid tight security.
The Pentagon said the Cape Ray is carrying out the work in international waters in the Mediterranean but would not disclose details of the ship's location.
US officials have insisted the operation will not pose a serious risk to the environment and that elaborate precautions have been undertaken.
The 650-foot (197.5 metre) US cargo ship has a crew of 35 civilians operating the vessel and a 63-member team in charge of the hydrolysis units, as well as a security team on board.
The hydrolysis machines mix heated water and other chemicals to break down the lethal agents into toxic materials that pose less of a danger.
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