Hydrofluoric Acid and Other Impurities in Toxic Perfluorooctane Batches

Abstract

Purpose: The 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 Methods: We analyzed original packaged samples of Alatocta 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. Conclusions: HF 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 Relevance: In Alatocta batches different impurities show retinal toxicity. HF seems of particular importance of the acute toxicity of PFO.

Toxicity Threshold of Perfluorocarbon Liquids for Intraocular Use: Dose–Response Assessment of In Vitro Cytotoxicity of Possible Contaminants

“…Because the safety threshold of protonated impurity in PFCL for intraocular use was unknown, they sought to obtain liquid of the highest grade corresponding to protonated impurity content < 0.1 ppm and equivalent to the detection limit of the method. 16 The work of Sparrow et al, 22 demonstrated the toxicity of 1H-PFO at the perfluorocarbon-fluid interface in tissue culture by a qualitative assessment. These studies 7 , 22 indicated the level of impurities that were used for approval of perfluoro-n-octane from the U.S. Food and Drug Administration.…”

“…With respect to analyses of the contaminant profiles of the toxic AlaOcta batches conducted by Menz et al, 16 we might affirm that the toxicity of those batches could not be solely related to the presence of 1H-PFO or DFH, because their concentrations, which differed between the 59 and 875 ppm for 1H-PFO and between 29 and 45 ppm for DFH, were well below the cytotoxicity limit (CC 30 ) calculated in this study (CC 30 : 55712 ppm for 1H-PFO and 1173 ppm for DFH). Instead, the PFO batches containing PFOA at concentrations varying between 50 and 700 ppm and a mix of p -xylene isomers/ethylbenzene (82%:18% ratio) at 5 to 30 ppm 16 were surely toxic, because the quantity of these compounds was well above the cytotoxic limit found in this study (CC 30 : 17 ppm for PFOA; 1.21 ppm for p -xylene and 1.06 ppm for ethylbenzene). In addition, Srivastava et al 17 also analyzed the contaminants in the toxic AlaOcta batches and found that DFH was contained at nontoxic concentration, whereas PFOA was detected at concentrations that reduced the ARPE-19 cell viability of > 70% and thus were inevitably cytotoxic.…”

“… 8 Subsequently, 1H-perfluorooctane (1H-PFO) and perfluoro-2-n-butyltetrahydrofuran were also found as impurities in the toxic batches by other investigators. 16 , 17 …”

“…8 Subsequently, 1H-perfluorooctane (1H-PFO) and perfluoro-2-n-butyltetrahydrofuran were also found as impurities in the toxic batches by other investigators. 16,17 This study focused on the assessment of the cytotoxicity of p-xylene, ethylbenzene, PFOA, DFH, 1H-PFO and perfluoro-2-n-butyltetrahydrofuran, which were previously detected in the toxic AlaOcta batches. 8,16,17 Moreover, we tested the cytotoxicity of the partially hydrogenated PFO analogue 1H,1H,1H,2H,2Hperfluorooctane (5H-PFO) 18 and hexafluoro-1,2,3,4tetrachlorobutane, a solvent used for fluorination processes.…”

Reflectometry Reveals Accumulation of Surfactant Impurities at Bare Oil/Water Interfaces

“…It is unlikely that the observed impurities are introduced through the PFO itself, because the only PFO-based impurities potentially detectable by XRR and NR would be under-fluorinated (i.e., partially hydrogenated) molecules of amphiphilic character, which are not among the common impurities in PFO [69]. Moreover, there is considerable variability between the different samples regarding the obtained density deficits D and adsorbed amounts DHC even though PFO was introduced into the measurement cells from the same original bottle for samples 1, 2, and 4.…”