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HomeMy WebLinkAboutDEQ-CFW_000708660 z©c� loxicolo;y Reports 2 (2015) 939-949 Contents lists available at S(icnceD roc! n Toxicology Reports journal homepage: www.elsevier.com%locate%toxrep Evaluation of chronic toxicity and carcinogenicity of ammonium CrossMark 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate in qV Sprague-Dawley rats J.M. Caverly Rae , % Lisa qraig 11, Theodore W. Slone11, Steven R. Frame', L.William Buxton I - Gerald L. Kennedyd �I Z120 / e F2*,g_ DZO�& k4-&#) MU 5�;, �!ti a E I. du Pont de Nemours and Company, Inc., Haskell Global Centers for Health & Environmental Sciences, Newark, DE 19714, USA n MPI Research, Inc., Mattawan, MI49071, USA C E 1, duPont de Nemours and Company,. Inc., Chemicals and Fluoroproducts, Wilmington, DE 19805, USA d Consultant to DuPont Company, Wilmington, DE 19805,USA ARTICLE I NFO A B S T R A C T Article history: Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, developed for use as a polymeriza- Received 30 March 2015 tion processing aid in the manufacture of fluoropolymers, was tested for its potential chronic toxicity Received in revised form 4 May 2015 and carcinogenicity in a 2-year oral dosing study in Sprague-Dawley rats. Male rats were given daily Accepted Dune 2015 Available online 30 June 2015 doses of either 0, 0.1,1 or 50 mg/kg; females were given either 0, 1, 50 or 500 mg/kg. Body weights, food consumption and clinical signs were monitored daily; clinical pathology p g y; p gy was conducted at designated intervals and animals were given a complete pathological evaluation after 12 months and 24 months of Keywords: o mersxicity dosing. Normal survival was seen in all groups, no abnormal clinical signs were seen, and body weight Chronic toxicity and carcinogenicity study Cho gain was reduced only in female rats at 500 mg/kg. Both sexes at the high dose had mild decreases in Sprague-Dawley rats red cell mass which were somewhat more pronounced in females. Clinical pathology indicative of liver PPARtr agonist injury was present in males that received 50 mg/kg and correlated with histomorphological liver changes that included both hypertrophic and degenerative/necrotic lesions. Similar histomorphological lesions were seen in the livers of females at 500mg/kg. Previous shorter term toxicity studies have identified this chemical as a PPARot agonist and the finding of benign tumors of the liver, pancreas and/or testes in males at 50 mg/kg and females at 500 mg/kg is consistent with the rat response to peroxisome prolifera- tors and is of questionable human relevance. Changes in the kidney, tongue, and stomach were observed only at the highest dose of 500 mg/kg in females. The no -observed -adverse -effect -level in this study lies between 1 and 50 mg/kg for males and between 50 and 500 mg/kg for females. © 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (ilttp:/,crc ativeeoinrions.orjiic�nses; by/4.t)%), 1. Introduction Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)- propanoate (CAS 62037-80-3) is a white/colorless solid with a sublimation point of 130-140' C, a decomposition point of 150-160 - C, a density of approximately 1.7 g/cm3 at 20 C, and a very low vapor pressure of approximately 0.01 Pa at 201C [10]. The chemical has been developed for use as a polymerization processing aid in the manufacture of fluoropolymers. The acute toxicity profile includes both an oral LD50 of 1750 and 3129 mg/kg in male and female rats, respectively, and 1030 mg/kg in mice (females). The dermal LD50 in rats is greater than 5000 mg/kg. By the inhalation route, the chemical has an acute LC50 of greater * Corresponding author. Tel.: +1 3024514591.e��ta than 5200 mg/m3 in rats exposed for 4 h. As tested in rabbits, it is highly irritating to the eye but is not a skin irritant nor is it a sensitizer as tested by the mouse local lymph node assay. The material is not genotoxic based on a battery of tests including Ames and chromosome aberration in -vitro studies and mouse micronucleus, mouse bone marrow chromosomal analysis and rat unscheduled DNA synthesis in -vivo studies [ 10]. The compound is rapidly and completely absorbed following oral administration in both rats and mice, is not metabolized, and is eliminated almost exclusively in the urine. In the cynomolgus monkey given a single intravenous dose, the chemical was rapidly eliminated, no sex differences were seen, and a biphasic pattern of elimination was present. Based on oral studies in rats and mice, and intravenous studies in rats and primates, elimination of the test substance is most similar and more rapid in primates and rats, with mice having a comparatively longer clearance time. Clearance Imp: dk.day.org%10.1016 j.toxrep.2015.06.001 2214-7500/0 2015 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http:;-C)eeLitIVCDI.u,1ons org licenses by 4.0 ). DEQ-CFW 00070866 Toxicology 340 (2016) 1-9 �F Contents lists available at Sciencedirect' f� 10KIDER . d k Toxicology E1,S1-•V1f,K journal homepage: www.elsevier.com/locate/toxicol Absorption, distribution, metabolism, excretion, and kinetics of 2,3,3,3- * CrossMark tetrafluoro-2-(heptafluoropropoxy)propanoic acid ammonium salt following a single dose in rat, mouse, and cynomolgus monkey Shawn A. Gannon", William J. Fasanob, Michael P. Mawn`, Diane L. Nabbb, Robert C. Buck', L. William Buxton', Gary W. Jepsona, Steven R. Frame 'The Chemours Company, Wilmington, DE, USA b E 1. duPont de Nemours and Company, Haskell Global Centers for Health & Environmental Sciences, Newark, DE 19714, USA `E L DuPont de Nemours and Company, Wilmington, DE, USA Article history: Received 23 September 2015 Received in revised form 14 December 2015 Accepted 23 December 2015 Available online 29 December 2015 Keywords: Fluoropolymer ADME Rodent Monkey Pharmacokinetics Toxicokinetics 1. Introduction ABSTRACT Ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate has been developed as a processing aid used in the manufacture of fluoropolymers. The absorption, distribution, elimination, and distribution (ADME) and kinetic behavior of this substance has been evaluated in rats, mice, and cynomolgus monkeys by oral and intravenous routes of exposure and studied in both plasma and urine. The test substance is rapidly and completely absorbed in both rats and mice and both in vivo and in vitro experiments indicate that it is not metabolized. The test substance is rapidly eliminated exclusively in the urine in both rats and mice, with rats eliminating it more quickly than mice (approximately 5 h elimination half-life in rats, 20 h half-life in mice). Pharmacokinetic analysis in monkeys, rats, and mice indicate rapid, biphasic elimination characterized by a very fast alpha phase and a slower beta phase. The beta phase does not contribute to potential accumulation after multiple dosing in rats or monkeys. Comparative pharmacokinetics in rats, mice, and monkeys indicates that the rat is more similar to the monkey and is therefore a more appropriate rodent model for pharmacokinetics in primates. 2015 Elsevier Ireland Ltd. All rights reserved. The widespread presence of long -chain perfluoroalkyl acids (PFAAs) such as perfluorooctane sulfonate (PFOS) and perfluor- coctanoic acid (PFOA) has spurred a move to alternative fluorinated substances which have more favorable environmental and biological properties, most notably rapid elimination from living systems (Ritter, 2010; Buck et al., 2011; US EPA, 2006). Per - and poly -fluorinated ether carboxylates have been developed as alternative polymer processing aids for the aqueous emulsion polymerization of tetrafluoroethylene (TFE) and other fluorinated monomers in the synthesis of fluoropolymers (Buck, 2015; Buck et al., 2011; Gordon, 2011). They have replaced ammonium perfluorooctanoate which was historically used for this purpose (Feiring, 1994). * Corresponding author at: The Chemours Company, 1007 Market Street, Wilmington, DE, 19898, USA. E-mail address: shawn.a.ginnonCDchemours.com (S.A. Gannon). http: j /dx.do i.org,'l0.101G/j.tox.2015.12.006 0300-483X/© 2015 Elsevier Ireland Ltd. All rights reserved, rn.;t Ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propa- noate has been developed as a processing aid used in the manufacture of fluoropolymers. The acid form is a liquid and the ammonium salt is a solid at ambient temperature (20 oQ. Both are infinitely soluble in water above the pKa (2.84) of the acid. An aqueous solution is made and used in the fluoropolymer manufacturing process. The processing aid is either captured for re -use or thermally destroyed during fluoropolymer processing (Brothers et al., 2009). Some fluoropolymer aqueous dispersions that contain the processing aid are used to coat surfaces such as metal for making non-stick cookwear. The fluoropolymer is sintered onto the substrate surface at temperatures >265 °C. As shown in Table 1, the processing aid decomposes at 150-160 °C. The objective of the present study was to determine the absorption, distribution, metabolism and elimination (ADME) profile following oral and/or intravenous dosing of ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate, [Fig. 1, CF3CF2CF20CF(CF3)COOH•NH3, CAS# 62037-80-31 in the rat, mouse and cynomolgus monkey. The chronic toxicology and carcinogenicity of this test substance was recently described (Rae et al., 2015), as was the aquatic toxicology (Hoke et al., 2015). w4t S XA� kA*L__ DEQ-CFW 00070867 J�q 42- .00 k ruf� DEQ-CFW 00070868