C6-Perfluorinated Compounds: The New Greaseproofing Agents in Food Packaging
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Due to their oleophobic and hydrophobic properties and stability, perfluorinated compounds (PFCs) are used in many applications, particularly as greaseproofing agents for food contact. However, PFCs 8-carbons in length or greater (C8-PFCs) have raised concerns regarding environmental biopersistence, bioaccumulation in humans, and potent toxicity that have resulted in their gradual phase-out for food contact use. Industry has replaced C8-PFCs with shorter-chained C6-based greaseproofing agents, which are intended to have the same favorable physicochemical properties without the problematic toxicological effects in humans and wildlife. Compared with the large body of data available for C8 compounds, however, the available database on toxicity and exposure to the C6 compounds is fairly limited. This article summarizes the information in this database, focusing on aspects of human exposure and potential health risks associated with two types of C6 PFCs found in food packaging: perfluorohexanoic acid (PFHxA) and 6–2 fluorotelomer alcohol (C6-FTOH).
KeywordsPerfluorinated Fluorotelomer PFHxA Perfluoroalkyl Perfluorohexanoic Perfluorohexylethanol C6-FTOH Perfluorocarboxylates Food packaging
Perfluorinated compounds (PFCs) are composed of an alkyl chain with all of the hydrogens replaced by fluorine. This perfluorinated alkyl chain is bonded to another functional group, such as an acid, in the case of perfluorocarboxylic acids (PFCAs), or an alcohol (FTOH). Their hydrophobic and hydrophilic properties make them useful as surfactants in emulsion reactions, as reactants to make low-molecular weight perfluorinated products, and as monomers in higher molecular weight polymers. These products are used in microwave popcorn bag susceptors and greaseproofing films for paper and paperboard used in contact with oily foods, such as fast food containers and pizza boxes, as well as for other applications. While PFCAs and FTOHs are not specifically regulated by the US Food and Drug Administration (FDA), PFCAs are regulated as indirect food additives for food contact use by the FDA as surfactants and in the polymerization of high-molecular weight food contact substances (FCSs) under the 21 Code of Federal Regulations (CFR) sections 177.1380, 177.1550, 177.1615, 177.2400, and 177.2510. The use of PFCAs in the manufacture of low-molecular weight perfluorinated paper coatings was authorized in several listings for FCSs in 21 CFR 177.170 and 177.180 and Food Contact Notifications (FCNs) . FTOHs are components of high-molecular weight polymeric FCSs used as coatings, which are the subject of several effective FCNs  for their use as greaseproofing agents in food-contact paper and paperboard.
Uses and Routes of Exposure
As stated above, C6-perfluorinated telomers have similar uses to their long-chain counterparts. However, unlike the long-chain PFCs, the C6-PFCs do not appear to be used in the manufacture of non-stick cookware. It should also be noted that long-chain PFCs usually comprise a mixture of fluorotelomers varying in perfluorinated carbon length from C6 to C12 ; additionally, these mixed-chain-length telomers can be transformed in mammals  and in the environment [8, 9] to PFHxA and to perfluoroheptanoate (PFHpA). As such, it should be emphasized that levels of PFHxA measured in various media, including human bodily fluids and tissues, could originate from a variety of sources, including C6- and long-chain PFCs and FTOHs, and the presence of PFHxA in these media can only rarely be directly extrapolated to direct exposure to PFHxA itself. Therefore, the recent replacement of the long-chain PFCs with C6-PFCs is unlikely to be reflected in bodily fluid PFHxA levels from human biomonitoring studies, as exposure to PFHxA from biotransformation of the C6-PFCs would simply substitute for exposure to PFHxA from biotransformation of the long-chain PFCs. Regarding C6-FTOH, studies have rarely attempted to quantify C6-FTOH content in environmental media or human tissues, except for indoor air, due to its high volatility. However, since C6-FTOH was likely present as a contaminant and biotransformation product of long-chain PFCs, C6-FTOH tissue levels are also unlikely to change significantly as a result of the replacement of long-chain PFCs with C6-PFCs.
Studies have detected PFHxA in surface waters of Victoria Harbor in Hong Kong [10•] and European riverine discharge  at levels of 0.15–2.24 ng/L and 2.2–32 ng/L, respectively. There are conflicting data concerning the presence of PFHxA in foods and beverages, with one critical review concluding that C6 compounds were not found at detectable levels in any type of food analyzed  except for low levels of PFHpA in pizza (2 ng/g), microwave popcorn (1.5 ng/g), tap water (0.64–3.02 mg/g), and bottled water (0.4 ng/g). Likewise, a recently published total diet study conducted in France  reported measurable levels of PFHxA at levels less than 1 ng/g in all of the food types sampled, with the highest reported levels in ‘sweet and savory biscuits and bars’ (0.915 ng/g), pastry and cakes (0.791 ng/g), and dairy-based desserts (0.583 ng/g); and an European Food Safety Authority (EFSA) scientific report summarizing the results of an analysis of 4,881 samples derived from various foodstuffs collected during the period 2000–2009 reported detectable levels of PFHxA in 0.9 % of samples . In contrast, Zhang et al. (2011) reported levels of <0.1–0.97 ng/g PFHxA in freshwater fish and seafood [15•], and a study conducted in Catalonia, Spain reported levels of ~0.1 ng/g PFHxA in veal, fried chicken nuggets, and frankfurters . There are no data on levels of possible precursors to PFHxA (FTOH, PFCs) in food and drinking water. As may be seen from the discussion in the next section, exposure to these compounds may also contribute to PFHxA body burden.
PFHxA is rapidly and completely absorbed from the gut after oral administration, with no saturation of absorption noted at high doses, and is rapidly eliminated from the body via the urine without being metabolized [17••] in rats, mice, and monkeys, with only negligible percentages of the dose excreted in feces. Notably, and unlike the long-chain PFCA compounds, PFHxA is not a substrate for the renal tubule organic anion transporters (OATs) and thus is not reabsorbed from the renal filtrate, which accounts for the high efficiency of urinary elimination of PFHxA compared with longer-chain PFCAs . PFHxA does not significantly accumulate in any tissue examined, except for the liver [19•], which had PFHxA levels 4- to 8-fold greater than plasma levels in mice in one study. Systemic half-lives of PFHxA in male and female rats were estimated to be 1.5–1.7 hours and 0.5–0.7 hours [17••], respectively, with elimination half-lives of 1–2 hours in both mice and rats [20••]. Elimination half-lives in cynomolgus monkeys and humans were calculated to be 1–2 days  and 14–49 days [20••], with no apparent gender differences. Moreover, the elimination half-lives for PFHxA were proportional to bodyweights, indicating similar volumes of distribution and elimination mechanisms between species [20••]. The C6-FTOH similarly has extremely short elimination half-lives in vivo, with 75–90 mol-% of the oral dose eliminated within 24 hours . Studies conducted in rat liver microsomes observed that PFHxA and the 5:3 acid were the primary stable metabolites produced from the C6-FTOH [23••]; other stable metabolic products included the 4:3 acid, perfluorobutanoate, perfluoropentanoate, and PFHpA, all of which would be rapidly excreted in the urine. The 6–2 fluorotelomer iodide and the 6–2 fluorotelomer methacrylate were rapidly metabolized to C6-FTOH in rat liver microsomes [23••] and rat hepatocytes [24•], respectively. Perfluorinated FCSs, such as the perfluoroalkyl phosphate surfactants, can also be metabolized in vivo to their FTOH components and the corresponding FTOH metabolites . Collectively, these data indicate that direct dietary exposure to perfluorinated FCSs or their perfluorinated monomeric precursors may produce toxic effects similar to exposure to the FTOH itself. As such, data from toxicity studies conducted with PFCAs and particularly with the FTOHs are directly relevant to the safety assessment of direct dietary exposure to perfluorinated polymeric FCSs.
PFHxA Biomonitoring Data
Several studies have examined serum levels of PFCs in various populations; most of the available data concern levels of C8-PFCs in biological fluids, with very few papers reporting levels of C6 compounds. There are several papers that have reported that PFHxA levels in human biological fluids (serum, milk) are below methodological limits of detection. For instance, a survey of PFC levels in umbilical cord blood samples from hospital deliveries in Ottawa, Canada reported that PFHxA levels were below the limit of detection in the majority of tested samples [26•]. Another study conducted in the general population in Hong Kong only found detectable levels of PFHxA in 40 % of the serum samples [10•], and PFHxA was not detected in any of the serum samples derived from primiparous Swedish women sampled during pregnancy and nursing [27•]. Other studies, however, have reported extremely low, but measureable, levels of PFHxA in bodily fluids from the general population ranging from 0.25 to 3 ng/ml [28•, 15•], with most samples <1 ng/ml. There is little difference in age range or limit of detection between studies that find PFHxA in sera/bodily fluids versus those that do not, and the studies were conducted over a similar time period. Thus, these differences in detection of PFHxA between studies should not be attributed to changing environmental levels. PFHxA was not detected in samples of breast milk [29•] but was detected in serum and urine taken from 5- to 13-year-old South Korean children and serum from adults of the same population [30•]. Autopsy samples of brain, lung, and liver from the general population in Catalonia, Spain reported PFHxA at mean levels of 180, 50.1, and 115 ng/g tissue, respectively . The relatively high tissue levels found in the Spanish study are difficult to reconcile with the extremely low levels found in serum in most studies and with the data from pharmacokinetic studies in animals, which did not find significant accumulation of PFHxA in any tissue examined, except for low levels in liver. It is possible that the high levels of PFHxA found in this study reflect exposure to PFHxA precursors that were metabolized to PFHxA in situ, rather than to PFHxA itself. In fact, the extremely high levels of PFHxA found in the brain and lung in that study are consistent with possible inhalation exposure to the C6-FTOH, which has been shown to be present in ambient air at levels of up to 196 pg/m3 . Given the fact that the subjects in the Spanish study were co-exposed to PFHxA and to both C6-PFC and long-chain PFC during life, untangling the contributions of each of these exposures to the observed tissue levels would be extremely difficult and would confound any comparison with pharmacokinetic studies conducted with purified PFHxA in animals.
In conclusion, most studies report extremely low or undetectable levels of PFHxA in serum and other bodily fluids in the general population and, with a few exceptions, in foodstuffs consumed in the diet. Biomonitoring data for the C6-FTOH and its metabolic byproducts, with the exception of PFHxA and PFHpA, are unavailable, however.
Systemic and Reproductive Toxicology
Compared with the extensive toxicological database available for the long-chain PFCs, relatively few mammalian toxicity studies have been conducted with the C6 compounds, and all of these have been conducted in rodents. For PFHxA, 90-day  subchronic and 2-year [34••] oral toxicity studies have been conducted in rats with the free acid, at dose ranges of 0, 10, 50, and 200 mg/kg/day for the subchronic study and doses of 0, 2.5, 15, and 100 mg/kg/day (males) and 0, 5, 30, and 200 mg/kg/day (females) in the chronic study. Ninety-day oral studies have also been conducted in rats with sodium PFHxA  and C6-FTOH [36••] at dose ranges of 0, 20, 100, and 500 mg/kg/day for Na PFHxA and 0, 5, 25, 125, and 250 mg/kg/day of C6-FTOH. One-generation reproductive toxicity and teratogenicity studies have been conducted with sodium PFHxA  and C6-FTOH [37••] in rats using the same dose ranges as the subchronic studies cited above, and a one-generation reproductive toxicity study has been conducted with PFHxA ammonium salt in mice [38••] using dose ranges of 0, 100, 350, or 500 mg/kg/day (phase I) or 0, 7, 35, or 175 mg/kg/day (phase II). A 14-day study conducted with the 6–2 methacrylate in rats is also available [24•]. The subchronic [39••], chronic , and developmental  toxicity studies conducted with PFHxA and C6-FTOH were all compliant with their respective guidelines in the FDA’s Redbook. In particular, the subchronic and chronic studies gavaged rats with the test compound for 90 days and 104 weeks, respectively, and measured the following endpoints: bodyweight and feed consumption; biochemical parameters in serum and urine; hematological parameters; organ weights and histopathology; ophthalmology; and neurological function via conduct of a Functional Observational Battery (FOB).
The subchronic [33, 35, 36••] and developmental/reproductive toxicity [35, 37••, 38••] studies demonstrate that the C6 compounds share some similarities in their toxicological profiles with the C8 compounds (see below), except that PFHxA appears to be at least an order of magnitude less potent than perfluorooctanoate (PFOA). Common findings in the above-cited 90-day studies included mortality and/or decreased bodyweights, hepatocellular hypertrophy and increased liver weights, increased kidney weights, and hematological changes indicative of mild anemia at the high doses tested in these studies. However, unlike PFOA, PFHxA did not induce neoplastic effects in any organ in the chronic study [34••].
Studies noted either decreased survival or decreased bodyweights with PFHxA or C6-FTOH administration [33, 35, 36••]. Decreased survival and early mortality was noted at the highest doses tested in the chronic study [34••] with PFHxA of 100 mg/kg/day (males) and 200 mg/kg/day (females), with early mortality noted in both sexes and decreased survival noted in females only. The early mortality was associated with renal papillary necrosis and renal tubular degeneration. The C6-FTOH also induced mortality in both sexes at 250 mg/kg/day in the subchronic study, the highest dose tested, and in one female at 125 mg/kg/day [36••]. Bodyweights were not affected by treatment in either study. In contrast, significantly decreased bodyweights were noted in the subchronic studies conducted with PFHxA in males at doses of ≥50 mg/kg for the free acid and 500 mg/kg for the Na salt [33, 35], with no mortality noted.
Hepatocellular hypertrophy with increased liver weight parameters was one of the most sensitive effects noted in the subchronic studies [33, 35, 36••] and in the 14-day study [24•]; lowest observed effect levels (LOELs) from 90-day studies for this effect were 25 mg/kg/day for C6-FTOH and 100–200 mg/kg/day for PFHxA in males and 125 mg/kg/day for C6-FTOH and 500 mg/kg/day for PFHxA in females. In the chronic study [34••], hepatocellular hypertrophy was not evident at doses of up to 100 mg/kg/day (males) and 200 mg/kg/day (females); however, hepatocellular necrosis and hepatic congestion were noted in high-dose males and females. The hepatocellular necrosis observed after 104 weeks of PFHxA administration is likely the result of the enzyme induction and peroxisomal proliferation that was noted in the 90-day study. The C6-FTOH also induced single-cell hepatocellular necrosis, oval cell/biliary hyperplasia, and periportal inflammation at ≥25 mg/kg/day in males and ≥125 mg/kg/day in females after 90 days of administration [36••]. In neither study were these changes accompanied by elevations in biochemical indicators of liver injury. Interestingly, while Loveless et al.  noted induction of peroxisomal proliferation at the same dose levels that induced hepatocellular hypertrophy, these changes were not accompanied by alteration in serum cholesterol or triglycerides. Indeed, while all of the studies noted hepatocellular hypertrophy with C6 administration, no consistent effects on serum cholesterol profiles were reported. Supporting this finding, recent studies observed that the potency of PFHxA at the human peroxisome-proliferator activated receptor (PPAR)α, activation of which is associated with decreased blood lipid levels, is approximately half the potency of PFOA in the human hepatocellular carcinoma cell line HepG2 [42•] and approximately six-fold less potent than PFOA in both mouse and human PPARα in transiently transfected COS cells [43•]. Additionally, the decreased retention of PFHxA in the liver compared with the longer-chained compounds such as PFOA greatly decreases its potency to induce hepatic peroxisomal proliferation in vivo . Concomitant with these findings, there was also no association of PFHxA serum levels (0.03 ng/ml median) with blood lipids in a Chinese population [45•].
Subchronic studies conducted with both PFHxA and C6-FTOH noted increased kidney weight parameters [33, 35, 36••]. Kidney weight parameters were increased only in males administered PFHxA for 90 days at ≥10 mg/kg , whereas Na PFHxA increased kidney weight parameters in both sexes at ≥100 mg/kg/day ; these increases occurred in the absence of histopathological changes. However, after administration for 104 weeks, PFHxA induced renal tubular degeneration and papillary necrosis accompanied by increased urine volume and decreased specific gravity in females at 200 mg/kg/day, indicating significant adverse functional alterations in renal concentrating ability [34••]. Therefore, it would appear that the increased kidney weights in males noted in the subchronic studies represented adaptive changes to PFHxA administration, whereas the free acid of PFHxA induced renal injury in females only after chronic exposure. The reasons for this gender-specific effect of PFHxA and difference in kidney-weight response in females between the free acid and the Na salt are not apparent. For the C6-FTOH, the increased kidney weights noted in the subchronic study were accompanied by adverse histopathological changes, and the kidney appeared to be as sensitive as the liver to the adverse effects of C6-FTOH in females, with renal tubular degeneration and necrosis evident at ≥125 mg/kg/day C6-FTOH in females and at 250 mg/kg/day in males [36••].
Decreased erythrocyte parameters (erythrocyte number, hematocrit, hemoglobin) and increased reticulocyte counts were noted in both subchronic and chronic toxicity studies conducted with PFHxA at the highest doses tested, indicative of mild anemia with concomitant regenerative responses [33, 35, 36••]. While this was noted in both sexes in the subchronic study , anemia was only noted in females in the chronic study [34••], and the decreased erythrocyte parameters did not persist through the study duration. In contrast, the C6-FTOH induced adverse changes in the same erythrocyte parameters in the same dose range and gender pattern as was observed for hepatotoxicity [36••]. This disparity in dose ranges for this effect between PFHxA and the C6-FTOH may reflect differences in mechanism of action, the additive effect of the adverse hematopoietic effects of the various metabolites of the FTOH, and/or mechanisms secondary to the renal toxicity of the FTOH.
Ameloblast degeneration and altered tooth mineralization were noted with both the C6-FTOH [36••] and the 6–2 methacrylate [24•]; the study authors speculated that fluoride released from metabolism of the test compounds was the causative agent for the observed changes, and increased urinary fluoride levels were noted at the same doses as the adverse effects on the teeth [36••]. These effects were not seen in any of the studies conducted with PFHxA [33, 35, 34••].
No observed adverse effect levels (NOAELs) for systemic toxicity of PFHxA in the 90-day studies were 20 mg/kg/day for the sodium salt  and 50 and 200 mg/kg/day for the free acid in males and females, respectively , which are considerably higher than the 90-day no observed effect level (NOEL) of 0.06 mg/kg/day reported for the ammonium salt of PFOA in rats . Similarly, the NOAEL levels for systemic toxicity in male and female rats for PFHxA in the chronic study [24•] were 15 and 30 mg/kg/day, respectively, whereas the bioassay conducted with ammonium PFOA in rats noted liver damage in treated rats down to the lowest dose tested of 1.5 mg/kg/day . In contrast, both the 90-day study conducted with the C6-FTOH [36••] and an oral 90-day study conducted with the C8 fluorotelomer alcohol (8–2 FTOH)  reported NOAELs of 5 mg/kg/day for systemic toxicity, indicating that decreased perfluorinated chain length of the FTOH did not decrease the toxic potency under the test conditions in short-term studies.
Reproductive toxicity studies were conducted with sodium PFHxA  and C6-FTOH [37••] in rats and ammonium PFHxA in mice [38••]. The studies conducted with PFHxA salt and C6-FTOH gavaged male and female CD rats for ~70 days prior to mating, and pregnant females through to lactation day (LD) 22. Separate teratology studies conducted with the sodium PFHxA and C6-FTOH gavaged pregnant rats on gestation days (GD) 6–20, with terminal necropsy on GD 21. The PFHxA study in mice gavaged pregnant ICR dams from GD 6 through LD 22.
There were no effects of sodium PFHxA  or C6-FTOH [37••] on any reproductive indices in rats at doses of up to 500 mg/kg/day and 250 mg/kg/day, respectively; decreased maternal bodyweights and bodyweight gains were noted in the teratology , but not the reproductive, cohort at 500 mg/kg/day PFHxA and in both cohorts at 250 mg/kg/day C6-FTOH [37••]. There were no effects of sodium PFHxA on reproductive organ weights or histopathology in the P0 generation. The only developmental effects of sodium PFHxA noted were a 17–18 % decrease in mean pup weight throughout the lactation period in the F1 generation in the one-generation study and 10 % decreased fetal weight in the teratology study at 500 mg/kg/day, the highest dose tested in both studies. For the C6-FTOH [37••], the reproductive study noted increased pup mortality and decreased pup weights at ≥125 mg/kg/day; increased incidences of delayed ossification and wavy ribs were noted in the teratology study at these doses. The NOELs for prenatal and postnatal toxicity in rats from these studies were 300 mg/kg/day PFHxA and 25 mg/kg/day C6-FTOH. In contrast, mice were far more sensitive to the effects of PFHxA. Decreased bodyweight gains during postnatal days (PNDs) 0–4 (≥350 mg/kg/d) and the entire lactation period (500 mg/kg/d) were noted in dams [38••]. Significant litter observations (mostly at ≥ 350 mg/kg/d) included increased incidences of stillbirths, increased whole litter loss on PNDs 0–3, decreased pup survival during lactation, decreased pup bodyweights, delayed eye opening, and reduced terminal bodyweights in F1 females and terminal bodyweight : liver weight ratios in F1 males. At 175 mg/kg/day, significant findings included increased numbers of stillborn pups and pups dying on PND 1 and decreased pup weight at PND 1. The NOEL for developmental toxicity of PFHxA salt in mice from the study is 35 mg/kg/day. The adverse effects noted on pup bodyweight, postnatal survival, and attainment of developmental landmarks are consistent with effects noted in mice after PFOA administration; however, the LOELs for these effects in the study conducted with PFHxA are at least two orders of magnitude greater than the respective LOELs for PFOA in mice, the most sensitive species , of 0.6 mg/kg/day and 1 mg/kg/day, respectively, emphasizing the decreased potency of the C6 compound compared with PFOA.
In summary, subchronic and chronic oral toxicity studies conducted with PFHxA (free acid and sodium salt) reported an array of toxicological effects that are broadly similar to those noted with PFOA: decreased bodyweights, hepatocellular hypertrophy and peroxisomal proliferation, and anemia. Kidney effects were more pronounced with PFHxA versus PFOA; but the data overall demonstrate that PFHxA is much less toxic than PFOA, with LOELs at least an order of magnitude higher for PFHxA than PFOA. Moreover, PFHxA was non-carcinogenic in rats and did not display the potent postnatal toxicity noted with PFOA in either rats or mice.
In contrast, the toxicological profile for the C6-FTOH is not as well characterized. Subchronic studies conducted with the C6-FTOH identify similar toxic endpoints to those identified for the 8–2 FTOH, with adverse effects on the teeth, the kidneys, the liver, and red blood cell homeostasis. However, the mortality noted during the C6-FTOH study was not seen with the 8–2 FTOH, and the adverse effects on the kidney were more severe in the C6-FTOH study. As such, while the toxicological profile for PFHxA itself appears less concerning than that for long-chain PFCAs, the toxicological profile and potency for the C6-FTOH may be similar to the long-chained FTOHs. Future studies are needed to confirm whether this is the case.
PFCAs and FTOHs have been used in a variety of applications, including food packaging. Human exposure to these compounds has been demonstrated, with diet as a significant contributor, although the significance of exposure from food packaging has not been elucidated. Due to concerns regarding the toxicological profile of C8-PFCs, industry has phased out use of this class of compounds, replacing them with C6-based PFCs. Although the existing toxicological database for the C6-PFCs is, as yet, comparatively sparse, these compounds do not appear to possess the biopersistence and potent systemic and reproductive toxicity that are characteristic of C8-PFCs as a class. Instead, data from animal and epidemiological studies indicate that C6-PFCs are rapidly and completely excreted and do not appear to accumulate in biological fluids. Of the two C6 compounds discussed in this article, PFHxA has been well characterized in rodent models. PFHxA has a similar profile of toxicological effects to PFOA based on in vivo subchronic studies in rodents; however, the lack of bioaccumulation in the liver significantly decreases the potency of PFHxA, leading to NOAEL values that are at least an order of magnitude higher than the respective NOAEL values for long-chain PFCs. Moreover, PFHxA has been demonstrated to be non-carcinogenic in rodents, unlike PFOA, and appears to be a far less potent postnatal toxicant. In contrast, significant data gaps remain in the toxicological profile of C6-FTOH. The pharmacological profile of this compound in humans and rodents in vivo is not well characterized, and data from biomonitoring studies determining levels of this compound or its metabolites in human biological fluids are lacking. Data on the chronic, reproductive, and developmental toxicity of this compound are also scanty, as there are no available studies examining the toxicological profile of the C6-FTOH in mice, which have been shown to be more sensitive to the toxicological effects of PFCs than rats. Given the fact that toxicity data for the FTOHs are highly pertinent to the safety evaluation of dietary exposure to perfluorinated PFCs, confirmation that the C6-PFC compounds are a safer alternative to the long-chain PFCs awaits data from appropriately designed studies conducted with the C6-FTOH that address these data gaps.
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Conflict of Interest
Penelope A. Rice declares that she has no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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