Potassium 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulphonate

Endpoint summary

Description of key information

The toxicokinetics of PFBSK+ was evaluated in three studies with exposure intravenously (IV) and three studies with exposure via oral gavage. The results of the studies were:

Intravenous:

The mean terminal half-life of PFBSK+ following a single IV dose was 3.5 to 4 days in male and female monkeys. In monkeys, urinary excretion was a major route of elimination of unchanged PFBSK+.

The mean PFBS half-life in male rats exposed to a single IV dose was 3.1 hours while female rats had a mean half-life of 2.4 hours.

The mean PFBS half-life in male monkeys exposed to a single IV dose ranged from 9.4 to 26 hours while females had half-life values ranging from 5.8 to 9.5 hours.

Oral:

The half-life of elimination of PFBSK+ following a single oral dose was 8 hours in male Sprague-Dawley rats.

Mice were fed a diet with PFBSK+ for 5 days. The highest levels of PFBSK+ were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. Whole-body autoradiography revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3d of exposure but appeared thereafter to level-off in most cases. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood. It did not appear that adequate time was allowed for absorption to take place (after dietary ingestion) hence complicated the overall tissue distribution (i.e., before, during, and after dietary exposure). It is worth noting that these animal tissues were not perfused hence the levels detected were largely attributed to the presence to blood inside the tissues.

Concentrations of PFBS in blood serum, liver, and eggs of Northern bobwhite quail exposed to dietary PFBS for 21 weeks were dose-dependent but were less than the administered dose, indicating biodiminution.

Additional information

The pharmacokinetics and urinary excretion of the test article were investigated in male and female cynomolgus monkeys. The study was not conducted in strict compliance with FDA GLP. However, the study was conducted according to the protocol and applicable standard operating procedures of the research laboratory. All study procedues, data recording and reporting were performed in a manner consistent with the standard of GLPs. Three male and three female monkeys were administered a single IV bolus dose of 10 mg/kg of test article. Urine and feces were collected for 24-hour intervals on the following days: prior to dose administration (Day -1; baseline), on Day 0 (0-24 hours postdose), and on Days 7 and 14. The volume of each urine sample was measured upon collection. Blood samples (approximately 2 mL) were collected from each primate at approximately 0 (predose) minutes; 2, 4, 8, 24, and 48 hours; and on Days 4, 7, 11, 14, and 31 postdose. Samples were collected into tubes without anticoagulant and were allowed to clot at room temperature. The blood samples were then centrifuged, and the serum separated and stored frozen (-20 °C or below) until analyzed by HPLC/MS/MS for levels of intact test article. The lower limit of detection of the analytical method was 0.5 ng/mL. No sex-related differences in serum concentrations of test article were apparent among the six dosed monkeys. In individual animals, the concentration of test article in serum ranged from 19,628 to 61,740 ng/mL at 2 hours after dosing (earliest time point). By 48 hours after dosing, the serum concentration of test article ranged from 463 to 8,172 ng/mL in individual monkeys. The test article was not detectable in serum collected from any monkey on Day 31 post dose. The serum concentration versus time data were best fit to a three-compartment model. Mean serum half-life values for the test article were 0.04, 0.55, and 4.0 days in male monkeys, and 0.06, 0.47, and 3.5 days in female monkeys. The mean AUC value calculated from serum concentrations of the test article was 24,258 or 35,401 ng.day/mL in male or female monkeys, respectively. The total body clearance of the test article was 511 mL/day/kg in male monkeys and 368 mL/day/kg in female monkeys. The volume of distribution at steady state (Vdss) was 254 or 255 mL/kg in male or female monkeys, respectively. For 5 of 6 monkeys, from 33.8 to 86.8% of the dose was recovered in urine within 24 hours after administration of the test article. On Day 14, individual monkeys excreted less than 0.01% of the dose within a 24-hour interval. Based on the results of the study, the mean terminal half-life values for the test article in male and female monkeys was 3.5 - 4.0 days. In monkeys, urinary excretion was a major route of elimination of unchanged test article.

 

The toxicokinetics of PFBS were evaluated in Sprague–Dawley rats (single exposure: 10 mg/kg via IV, repeated exposure: 50, 150, 300 mg/kg via oral gavage) and cynomolgus monkeys (single exposure: 10 mg/kg via IV). In the monkey study, the animals were observed twice daily for motality and moribundity. Clinical examinations were performed twice on each day of dosing and daily on non-dosing days. Detailed physical examinations were performed weekly. Individual body weights were recorded weekly. Blood samples were collected from all animals at 0 (prior to dosing), 1, 2, 4, 8, 24 and 48 hours following administration. In the single-dose rat study, all animals were observed twice daily for mortality and moribundity. For urinary excretion evaluation, 3 animals/sex-group were placed in plastic metabolism cages following dose administration and urine was collected on wet ice over the following intervals: 0-6h, 6-12h, and 12-24h post-dosing. Using the reamining animals, blood samples for determination of PFBS concentration in serum were collected from a retro-orbital sinus while animals were under isoflurane anesthesia from 3 animals/sex-group at 0.5 h, 1h, 1.5h, 2h, 4h, 8h and 24h after dose administration. In the repeated-dose study, all animals were observed twice daily for mortality and moribundity and weighed weekly. Blood samples were collected from retro-orbital sinus while animals were under isoflurane anesthesia from up to 3 animals/sex-group at 0 (pre-dosing), 1h, 2h, 4h, 8h, and 24h after the first (Day 0) and 26th (Day 25 dose. For urinary excretion evaluation, all surviving animals were placed in plastic metabolism cages following dose administration on Day 26 and urine was collected in wet ice over the following intervals; 0-6h, 6-12h and 12-24h post-dosing. Systemic exposure to PFBS was up to 8-fold (intravenous) and 4-fold (oral) higher for males than females and serum clearance of PFBS was more rapid in females than males; however, there was no appreciable difference in the extent or rate of urinary elimination between genders. The mean PFBS half-life in male rats exposed to a single dose was 3.1 hours while female rats had a mean half-life of 2.4 hours under the same conditions. Male monkeys had half-life values ranging from 9.4 to 26 hours while females had half-life values ranging from 5.8 to 9.5 hours following a single dose.

 

The objective of this study was to determine the serum half-life of elimination for the test article. Male Sprague-Dawley rats (N = 3/dose group/exposure period) received a single 30 mg/kg dose of the test compound in propylene glycol by oral gavage at a volume of 5 mL/kg body weight. The vehicle control group rats received a single dose of propylene glycol at a volume of 5 mL/kg. Urine was collected from all treatment groups on days 1-4 and stored for possible future analysis. Necropsies were performed at 4 hours (day zero), 28 hours (day one), and 100 hours (day four) post dose. The concentration of the test compound in serum and liver were monitored by the nonspecific method of total organic fluorine (TOF) analysis, which measures the amount of the parent compound plus any metabolites in these tissues. A limited number of sample collections were taken in this study, therefore, the apparent elimination half-life and the maximum tissue concentrations of TOF are best estimates based on the available data. The serum half-life of elimination of PFBS was approximately 7 to 8 hours. The molar percentage of total fluorine absorbed from the dose and present in serum and liver were estimated 4-, 28-, and 100- hours after dosing based on measured TOF concentration. The highest measured percentage of the test article were approximately 3% in the serum and 1.6% in the liver, four hours post dose. Based on the results of the study, the half-life of elimination of the test article is 8 hours.

 

Mice were fed a diet with 16 mg/kg 35S-labelled PFBS for 1, 3, or 5 days. Following dietary exposure of adult male C57/BL6 mice for 1, 3 or 5d to 16mg/kg/day 35S-PFBS, both scintillation counting and whole-body autoradiography (WBA) revealed the presence of PFBS in all of the 20 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. After 5d of treatment the highest levels were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. WBA revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3d of exposure but appeared thereafter to level-off in most cases. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood. It did not appear that adequate time was allowed for absorption to take place (after dietary ingestion) hence complicated the overall tissue distribution (i.e., before, during, and after dietary exposure).  It is worth noting that these animal tissues were not perfused hence the levels detected were largely attributed to the presence to blood inside the tissues.

 

Northern bowhite quail (Colinus virginianus) (16/sex/group) were exposed to dietary PFBS (0, 100, 300, 900 mg/kg diet) in feed for 21 weeks. Liver and blood samples were collected from surviving adult burds for PFBS analysis.  PFBS concentration was determined in the eggs. PFBS was present in liver and blood serum of adult quail in a dose-dependent manner. While there was a slight difference in liver and serum PFBS concentrations between male and adult female quail from each of the exposures, these differences were not statistically significant and were typically less than 1.5-fold. PFBS concentrations measured in blood serum were greater than that observed in the liver. The ratio between mean PFBS concentrations in blood serum and liver for both adult male and female quail ranged from 3.4 to 5.1 with a mean value of approximately 4. Serum PFBS concentration of both genders was approximately 6- to 13-fold less than that measured in diet while liver PFBS was approximately 30-to 56-fold less than that in the diet. Concentrations of PFBS in eggs were directly proportional to dietary concentrations and were also dependent on when the eggs were laid during the study. Concentrations of PFBS in eggs laid during the seventh week (lot G) were approximately 1.6-fold greater than that measured in eggs during the second week (lot B). Concentrations of PFBS in blood serum, liver, and eggs were dose-dependent but were less than the administered dose, indicating biodiminution.

Conclusion:

Based on the results of the studies, PFBSK+ is not expected to bioaccumulate in mammals.