Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 19 (2015) / Chapter Skim
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6 Tetrafluoroethylene Acute Exposure Guideline Levels
6 Tetrafluoroethylene Acute Exposure Guideline Levels
Pages 163-204
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From page 163... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
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The resulting renal cell necrosis and regeneration is thought to be responsible for renal neoplasms in rats following chronic exposure. In all cases where recovery was evaluated, surviving animals had evidence of recovery from renal lesions.
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From page 165... ...
A default intraspecies uncertainty factor of 10 also was applied because data on variability in the toxicokinetics of tetrafluoroethylene in humans are lacking and because of evidence that polymorphisms in several of the enzymes in the bioactivation pathway for this and related compounds might modify susceptibility. The total uncertainty factor was 100.
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From page 166... ...
Because AEGLs are applicable to rare events or a single once-in-a-lifetime exposure and because of the uncertainty in assessing excess cancer risk following a single acute exposure of 8 h or less, the acute toxicity values were used to set AEGL levels.
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From page 167... ...
Tetrafluoroethylene 167 TABLE 6-2 Chemical and Physical Properties of Tetrafluoroethylene Parameter Value References Synonyms Ethene, tetrafluoro; perfluoroethylene; HSDB 2012 FC-1114; Fluoroplast 4; TFE monomer CAS registry no. 116-14-3 HSDB 2012 Chemical formula CF2 = CF2 Matheson 1980 Molecular weight 100.02 HSDB 2012 Physical state Colorless gas HSDB 2012 o Melting point -131.15 C HSDB 2012 Boiling point -75.9oC HSDB 2012 o Solubility in water 159 mg/L at 25 C HSDB 2012 3 o Density/specific gravity 1.519 g/cm at -76 C HSDB 2012 Vapor density (air = 1)
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Renal lesions included degeneration and necrosis of the convoluted tubules. No further details were reported by the investigators.
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. Clinical signs included salivation and lethargy at 40,100 ppm and clear discharge from the nose and reduced response to sound at 78,700 ppm.
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Exposure Duration Effect Reference 3,500 30 min Reversible renal changes. Dilley et al.
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No clinical signs of toxicity were observed during treatment. Increases in renal and hepatic weight, reductions in serum alkaline phosphatase and glutamic pyruvic transaminase activity, and renal lesions were observed.
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Incomplete Haskell Laboratory 1977 5 d/wk, recovery of renal lesions at 3,510 ppm. 2 wk; killed 0 and 14 d postexposure F344 rat, 25 females/group 0, 31, 300, 6 h/d, No cell proliferation in the kidneys after one Keller et al.
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B6C3F1 mouse, 5/sex/group 0, 312, 622, 1,260, 6 h/d, No clinical findings; no effect on body weight or NTP 1997 2,500, 4,990 5 d/wk, weight gain; some organ weight differences in females 12 exposures over 16 d at ≥2,500 ppm; renal tubule epithelial cell karyomegaly in males at ≥1,250 ppm and in females at ≥ 2,500 ppm; no renal lesions at 312 or 612 ppm. B6C3F1 mouse, 48/sex/group 0, 312, 625, 1,250, 5 h/d, No clinical signs; no effect on body weight and weight NTP 1997 2,500, 5,000 5 d/wk, gain; no effect on organ weight; anemia in males at 90 d ≥2,500 ppm and in females at 5,000 ppm; polyuria at ≥2,500 ppm (both sexes)
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No biologically significant effects on cell proliferation were found after a single exposure. On test day 5, a statistically and biologically significant increase in cell proliferation (indicated by cell labeling following infusion with 5-bromo3ʹdeoxyuridine)
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No biologically significant effects on cell proliferation were observed after a single exposure. On test day 5, a statistically and biologically significant increase in cell proliferation (indicated by cell labeling)
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Renal tubule karyomegaly (enlargement of the cell nucleus) was observed in male mice exposed at 1,250 ppm or higher and in female mice exposed to 2,500 ppm or higher.
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activity in vitro in Chinese hamster ovary cells, with and without metabolic activation (Vlachos 1987)
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There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of renal tubule neoplasms, liver hemangiosarcomas, hepatocellular neoplasms, and mononuclear cell leukemia. There was clear evidence of carcinogenic activity in male and female B6C3F1 mice based on increased incidences of hepatic hemangiomas and hemangiosarcomas, hepatocellular neoplasms, and histiocytic sarcomas.
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From page 179... ...
. A single 6-h exposure to tetrafluoroethylene at 1,200 ppm was a no-effect concentration for renal lesions as evidenced by a lack of cell proliferation (Keller et al.
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. Renal lesions were also reversible in rats exposed at 1,200 ppm for 6 h/day for 12 days (Keller et al.
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Cell necrosis followed by chronic regeneration of the epithelium in the kidney (increased cell proliferation) results in greater opportunity for error in DNA synthesis and mutation (Cohen and Ellwein 1990; Cohen 1998)
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No empirical data on the relationship between concentration and exposure duration for a single end point were found. When such data are lacking, time scaling is performed using the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al.
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From page 183... ...
A default intraspecies uncertainty factor of 10 also was applied because data on variability in the toxicokinetics of tetrafluoroethylene in humans are lacking and because of evidence of polymorphisms in several of the enzymes in the bioactivation pathway for this and related compounds that might modify susceptibility (see Section 4.4.2)
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6.2. Animal Data Relevant to AEGL-2 Several acute exposure studies of tetrafluoroethylene reported effects meeting the definition of the AEGL-2.
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. Thus, 3,000 ppm was considered a NOAEL for irreversible renal lesions and was used as the point-of-departure for calculating the AEGL-2 values.
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Time scaling was performed as described for the AEGL-1 values. Because of the uncertainty associated with time-scaling a 4-h point-of-departure to a 10-min value, the 10-min AEGL-3 value was set equal to the 30-min AEGL-3 value.
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Because of the uncertainties inherent in assessing excess cancer risk following a single acute exposure at durations of 8 h or less, the acute toxicity values were used to set the AEGL values.
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of the American Industrial Hygiene Association (AIHA 2004, 2013) are higher than the AEGL values.
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The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing lifethreatening health effects. b TLV -TWA (threshold limit value–time-weighted average, American Conference of Governmental Industrial Hygienists)
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1998. Cell proliferation and carcinogenicity.
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197-86. Submitted to EPA, Washing ton DC, by Fluoroalkene Industry Group, Wilmington, DE with cover letter dated Ju ly 10, 1986.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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EPA Document No.
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Uncertainty factors: Total uncertainty factor: 100 Interspecies: 10, because data on interspecies differences in the toxicokinetics of tetrafluoroethylene are lacking Intraspecies: 10, because data on variability in the toxicokinetics of tetrafluoroethylene in humans are lacking and because of evidence that polymorphisms in several of the enzymes in the bioactivation pathway for this and related compounds may modify susceptibility Modifying factor: None Time scaling: Cn × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001)
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From page 195... ...
Uncertainty factors: Total uncertainty factor: 100 Interspecies: 10, because data on interspecies differences in the toxicokinetics of tetrafluoroethylene are lacking Intraspecies: 10, because data on variability in the toxicokinetics of tetrafluoroethylene in humans are lacking and because of evidence that polymorphisms in several of the enzymes in the bioactivation pathway for this and related compounds may modify susceptibility Modifying factor: None Time scaling: Cn × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001)
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From page 196... ...
Toxicity end point: Estimated lethality threshold in the hamster (4-h BMCL05 of 20,822 ppm) Uncertainty factors: Total uncertainty factor: 100 Interspecies: 10, because data on interspecies differences in the toxicokinetics of tetrafluoroethylene are lacking Intraspecies: 10, because data on variability in the toxicokinetics of tetrafluoroethylene in humans are lacking and because of evidence that polymorphisms in several of the enzymes in the bioactivation pathway for this and related compounds may modify susceptibility Modifying factor: None Time scaling: Cn × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001)
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Tetrafluoroethylene 197 APPENDIX B CATEGORY PLOT FOR TETRAFLUOROETHYLENE FIGURE B-1 Category plot of toxicity data and AEGL values for tetrafluoroethylene. TABLE B-1 Data Used in Category Plot for Tetrafluoroethylene Source Species ppm Minutes Category AEGL-1 27 10 AEGL AEGL-1 27 30 AEGL AEGL-1 22 60 AEGL AEGL-1 14 240 AEGL AEGL-1 9 480 AEGL AEGL-2 69 10 AEGL AEGL-2 69 30 AEGL AEGL-2 55 60 AEGL AEGL-2 34 240 AEGL AEGL-2 23 480 AEGL AEGL-3 420 10 AEGL AEGL-3 420 30 AEGL AEGL-3 330 60 AEGL (Continued)
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2000 Rat and 1,200 360 0, no renal cell proliferation mouse Odum and Green 1984 Rat 2,000 360 1, no renal effects Odum and Green 1984 Rat 3,000 360 1, nonsignificant clinical chemistry changes Odum and Green 1984 Rat 4,000 360 2, significant clinical chemistry changes Odum and Green 1984 Rat 6,000 360 2, renal necrosis For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal.
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From page 199... ...
, hepatic hemangiosarcoma (0/50, 0/50, 5/50, and 1/50) , renal tubule adenoma or carcinoma (single sections 0/50, 3/50, 1/50, and 5/50; single and step sections 0/50, 3/50, 3/50, and 10/50)
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. Because of the uncertainties inherent in assessing excess cancer risk following a single acute exposure of 8 h or less duration, the acute toxicity values were used to set the AEGL values for tetrafluoroethylene.
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Uncertainty factors/Rationale: Total uncertainty factor: 100 Interspecies: 10, because data on interspecies differences in the toxicokinetics of tetrafluoroethylene are lacking Intraspecies: 10, because data on variability in the toxicokinetics of tetrafluoroethylene in humans are lacking and because of evidence that polymorphisms in several of the enzymes in the bioactivation pathway for this and related compounds may modify susceptibility Modifying factor: None Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001)
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From page 202... ...
End point/Concentration/Rationale: NOAEL for renal necrosis (3,000 ppm for 6 h) Uncertainty factors/Rationale: Total uncertainty factor: 100 Interspecies: 10, because data on interspecies differences in the toxicokinetics of tetrafluoroethylene are lacking Intraspecies: 10, because data on variability in the toxicokinetics of tetrafluoroethylene in humans are lacking and because of evidence that polymorphisms in several of the enzymes in the bioactivation pathway for this and related compounds may modify susceptibility Modifying factor: None Animal-to-human dosimetric adjustment: Not applied Time scaling: Cn × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used (NRC 2001)
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From page 203... ...
. Because of the uncertainty associated with time scaling a 4-h point-of-departure to a 10-min value, the 10-min AEGL-3 value was set equal to the 30-min AEGL-3 value.
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