NIEHS report on the in vivo repeat dose biological potency study of 1,1,2,2-tetrahydroperfluoro-1-dodecanol (CASRN 865-86-1) in Sprague Dawley (Hsd:Sprague Dawley® SD®) rats (Gavage Studies)

Abstract

Background: 1,1,2,2-Tetrahydroperfluoro-1-dodecanol (10:2 fluorotelomer alcohol) is a member of the per- and polyfluoroalkyl class of compounds to which humans are widely exposed. Toxicological information on this class of chemicals is sparse. A short-term, in vivo transcriptomic study was used to assess the biological potency of 1,1,2,2-tetrahydroperfluoro-1-dodecanol.

Methods: A short-term in vivo biological potency study on 1,1,2,2-tetrahydroperfluoro-1-dodecanol in adult male and female Sprague Dawley (Hsd:Sprague Dawley® SD®) rats was conducted. 1,1,2,2-Tetrahydroperfluoro-1-dodecanol was formulated in acetone:corn oil (1:99) and administered once daily for 5 consecutive days by gavage (study days 0–4). 1,1,2,2-Tetrahydroperfluoro-1-dodecanol was administered at 10 doses (0, 0.07, 0.2, 0.7, 2, 6, 18, 55, 160, and 475 mg/kg body weight [mg/kg]). Blood was collected from animals dedicated for internal dose assessment in the 2 and 18 mg/kg groups. On study day 5, the day after the final dose was administered, animals were euthanized, standard toxicological measures were assessed, and the liver and kidney were assayed in gene expression studies using the TempO-Seq assay. Modeling was conducted to identify the benchmark doses (BMDs) associated with apical toxicological endpoints and transcriptional changes in the liver and kidney. A benchmark response of one standard deviation was used to model all endpoints.

Results: Several clinical pathology and organ weight measurements showed dose-related changes from which BMD values were calculated. In male rats, the effects included significantly increased relative liver weight, increased absolute liver weight, decreased reticulocyte count, increased thyroid stimulating hormone concentration, and decreased free thyroxine concentration. The BMDs and benchmark dose lower confidence limits (BMDLs) were 8.087 (4.336), 21.893 (10.337), 54.227 (30.205), 138.723 (20.376), and 142.469 (57.746) mg/kg, respectively. In female rats, the effects included significantly increased relative liver weight, increased alkaline phosphatase activity, increased absolute liver weight, decreased platelet count, increased monocyte count, increased absolute left kidney weight, increased large unstained cell count, increased absolute right kidney weight, and increased relative left kidney weight. The BMDs (BMDLs) were 5.372 (2.294), 6.461 (6.003), 8.801 (3.465), 16.335 (9.571), 20.731 (4.642), 56.634 (10.508), 58.894 (25.959), 72.145 (18.001), and 85.629 (17.286) mg/kg, respectively. Average 1,1,2,2-tetrahydroperfluoro-1-dodecanol plasma concentrations at 2 hours postdose were similar in male and female rats. At 24 hours postdose, the concentration decreased and fell below the limit of detection of the analytical method in the 2 mg/kg female rats. Half-lives estimated using the two time points were 6.65 and 8.96 hours for the 2 and 18 mg/kg male rats, respectively, and 6.12 hours for the 18 mg/kg female rats.

In the liver of male and female rats, no Gene Ontology biological process or individual genes had BMD median values below the lower limit of extrapolation (<0.023 mg/kg). The most sensitive gene sets in male rats for which a reliable estimate of the BMD could be made were nucleotide biosynthetic process and organic hydroxy compound transport with median BMDs of 5.235 and 5.978 mg/kg and median BMDLs of 2.666 and 3.303 mg/kg, respectively. The most sensitive gene sets in female rats for which a reliable estimate of the BMD could be made were internal protein amino acid acetylation and glutamine family amino acid metabolic process with median BMDs of 5.355 and 8.071 mg/kg and median BMDLs of 3.108 and 3.552 mg/kg, respectively. The most sensitive upregulated genes in male rats with reliable BMD estimates included Akr7a3, Ephx1, Me1, Cyp4a1, Anxa7, and Slc17a3 with BMDs (BMDLs) of 2.192 (1.593), 2.467 (1.828), 3.531 (2.076), 4.588 (2.345), 4.660 (2.970), and 5.147 (3.485) mg/kg, respectively. The most sensitive downregulated genes in male rats with reliable BMD estimates were Pck1, A2m, Loc100911545/A2m, and Zfp354a with BMDs (BMDLs) of 1.149 (0.548), 1.733 (0.972), 1.733 (0.972), and 1.785 (0.579) mg/kg, respectively. In female rats, the top 10 most sensitive individual genes were upregulated. These genes were Abcc3, Gsta2, Gsta5, Ephx1, Akr7a3, Ehhadh, Pir, Gclm, Dao, and Me1 with BMDs (BMDLs) of 5.019 (2.945), 5.153 (2.796), 5.153 (2.796), 5.233 (3.072), 5.348 (3.082), 5.355 (3.108), 6.124 (2.642), 8.034 (3.552), 8.071 (2.669), and 8.192 (2.618) mg/kg, respectively.

In the kidney of male and female rats, no Gene Ontology biological process had BMD median values below the lower limit of extrapolation (<0.023 mg/kg). The most sensitive gene sets in male rats for which a reliable estimate of the BMD could be made were regulation of myeloid leukocyte mediated immunity and response to progesterone with median BMDs of 144.319 and 145.437 mg/kg and median BMDLs of 57.694 and 104.718 mg/kg, respectively. The most sensitive gene sets in female rats for which a reliable estimate of the BMD could be made were innate immune response and activation of immune response with median BMDs of 57.313 and 78.645 mg/kg and median BMDLs of 37.882 and 45.596 mg/kg, respectively. No individual kidney genes in male rats had median BMD values <0.023 mg/kg. The most sensitive upregulated genes in male rats with reliable BMD estimates included Ugt2b7, Ephx1, Adgre1, Map2, Slc6a1, Naaa, Il1b, Cyp24a1, and Nsg1 with BMDs (BMDLs) of 4.139 (1.398), 12.509 (3.282), 119.065 (89.170), 145.437 (104.718), 145.445 (104.722), 151.002 (107.821), 153.991 (109.464), 189.111 (127.579), and 216.472 (166.237) mg/kg, respectively. One gene, Top2a, was downregulated with a BMD (BMDL) of 203.468 (108.442) mg/kg. In female rats, one individual gene, Mrc1, was downregulated and had a BMD value <0.023 mg/kg. The most sensitive genes with reliable BMD estimates were upregulated and included Ckap2, Ugt2b37, Slc51a, Ugt2b7, Bbox1, Adgre1, Clec4a, Cyp26b1, and Lilrb4 with BMDs (BMDLs) of 2.608 (0.997), 32.501 (7.520), 37.134 (11.007), 54.314 (15.595), 61.319 (39.473), 61.524 (39.671), 82.466 (47.872), 238.250 (181.323), and 350.991 (212.248) mg/kg, respectively.

Summary: Taken together, in male rats, the most sensitive gene set BMD (BMDL) median, individual gene BMD (BMDL), and apical endpoint BMD (BMDL) values that could be reliably determined occurred at 5.235 (2.666), 1.149 (0.548), and 8.087 (4.336) mg/kg, respectively. In female rats, the most sensitive gene set BMD (BMDL) median, individual gene BMD (BMDL), and apical endpoint BMD (BMDL) values that could be reliably determined occurred at 5.355 (3.108), 2.608 (0.997), and 5.372 (2.294) mg/kg, respectively. The BMD (BMDL) could not be determined for one individual gene and was estimated to be <0.023 mg/kg.