Higher concentrations are often used for finer vasculature. Gd(III) chelates do not pass the intact blood–brain barrier because they are hydrophilic. Thus, these are useful in enhancing lesions and tumors where blood-brain barrier is compromised and the Gd(III) leaks out. In the rest of the body, the Gd(III) initially remains in the circulation but then distributes into the interstitial space or is eliminated by the kidneys. Gadolinium(III) contrast agents can be categorized into:     The following gadolinium chelated contrast agents have been approved for human use by European Medicines Agency (EMA) and/or the U.S. Food and Drug Administration (FDA):  Anaphylactoid reactions are rare, occurring in about 0.03–0.1%. As a free solubilized aqueous ion, gadolinium (III) is somewhat toxic, but was generally regarded as safe when administered as a chelated compound. In animals the free Gd (III) ion exhibits a 100–200 mg/kg 50% lethal dose, but the LD50 is increased by a factor of 100 when Gd (III) is chelated, so that its toxicity becomes comparable to iodinated X-ray contrast compounds. The chelating carrier molecule for Gd for MRI contrast use may be classified by whether they are macro-cyclic or have linear geometry and whether they are ionic or not. Cyclical ionic Gd(III) compounds are considered the least likely to release the Gd(III) ion, and hence the safest. However, the use of some Gd(III) chelates in persons with kidney disease was linked to a rare but severe complication, "nephrogenic fibrosing dermopathy", also known as nephrogenic systemic fibrosis (NSF). This systemic disease resembles scleromyxedema and to some extent scleroderma. It may occur months after contrast has been injected. Patients with poorer kidney function are more at risk for NSF, with dialysis patients being more at risk than patients with chronic kidney disease. At present, NSF has been linked to the use of four gadolinium-containing MRI contrast agents. The World Health Organization issued a restriction on use of several gadolinium contrast agents in November 2009 stating that "High-risk gadolinium-containing contrast agents (Optimark, Omniscan, Magnevist, Magnegita, and Gado-MRT ratiopharm) are contraindicated in patients with severe kidney problems, in patients who are scheduled for or have recently received a liver transplant, and in newborn babies up to four weeks of age."