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Abstract
PurposeThe complications with cytotoxic perfluorooctane (PFO) batches reported in 2015 were attributed to reactive underfluorinated impurities whose chemical identity and behavior still need to be clarified.Material and MethodsWe analyzed original packaged samples of Ala®octa batches involved in several reported cases of retinal toxicity. (A) The impurity profile was determined. (B) pH and fluoride ion content were measured. (C) Extraction with olive oil was performed to investigate differences in lipophilia among perfluorinated liquid (PFCL) as a measure for penetration of lipophilic cell membranes followed by measurements (A) and (B).Results(A) The detected impurities can be divided into: (1) reactive underfluorinated compounds and their degradation products including hydrogen fluoride (HF), (2) nonreactive underfluorinated compounds, (3) surface active compounds, (4) nonreactive fluorinated compounds, and (5) leachables from primary packaging components. The highest acute toxic potential is associated with the impurities of group (1). (B) HF was detected as a degradation product of reactive underfluorinated impurities by relying on the pH values and fluoride ion content of the water extracts. (C) Lipophilic impurities dissolved in PFO migrate into lipophilic extraction medium. In particular, HF is rapidly transferred in this way.ConclusionsHF as degradation product of unstable or reactive underfluorinated contaminants seems of particular importance triggering the acute toxicity of affected PFO. Contamination related toxicity and unwanted side effects can only be reliably excluded via analytical controlled multistage, high-purification processes.Translational RelevanceIn Ala®octa batches different impurities show retinal toxicity. HF seems of particular importance of the acute toxicity of PFO.
Highlights
Hydrogene fluoride (HF) seems of particular importance of the acute toxicity of PFO
After decades using perfluorinated liquids (PFCL) successfully in vitreoretinal surgery, there have been repeated reports of retinal toxicity caused by individual batches and different manufacturers of these products since 2013
The retinal toxicity of hydrogen-containing PFCLs was reported by Sparrow at al.[7] and Chang et al.[8] independent of the use of the H-value to characterize underfluorinated impurities
Summary
A commercial PFO, batch (PFO 33/15), with an H value , 10 ppm, manufactured and highly purified by Pharmpur GmbH (Koenigsbrunn, Germany), served as reference material. 0008 was used as the extraction agent to extract water-soluble components. Chem., Seelze, Germany, 75343-1L, Lot: BCBM9115V) was used as an extracting agent. To prepare external standard solution for quantifying detected impurities, the following materials were used: Dimethylbenzene mixture of isomers (VWR International GmbH, Darmstadt, Germany, 28975.291, Lot: 17K204015). 1H-PFO (Apollo Scientific Ltd., Manchester, United Kingdom, PC6140B, Lot: AS421860). Methyl-perfluorooctanoate (Alfa Aesar, Thermo Fisher Scientific, Karlsruhe, Germany, B23856, Lot: FA014458). Perfluoro-2-n-butyltetrahydrofurane (ABCR GmbH, Karlsruhe, Germany, AB103602, Lot: 1216897)
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