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Activity: Aerosol propellant, US EPA List 4B Inert (Halogenated organic)
Structure:

Adverse Effects:
Blood
Body Weight Decrease
Bone
Brain
CNS
Endocrine: Testicular
Eye
Heart
Kidney
Liver
Lung
Ringing in Ears
Tremors
Environmental

Blood (click on for all fluorinated pesticides)

HFC-134a (1,1,1,2-Tetrafluoroethane): Subject #3 was the first volunteer exposed to HFC-134a. The exposure concentration was 4000 ppm (0.4% v/v) and was scheduled to last for 30 minutes with a 5-minute postexposure evaluation period as was accomplished in the Halon 1301 portion of the study. Approximately 4.5 minutes into the exposure, the subject lost consciousness and both pulse and blood pressure dropped to zero. The exposure was immediately aborted and the subject was removed from the exposure apparatus. Medical personnel intervened and after pulse and blood pressure were restored the subject was administered 100% oxygen. Blood pressure and pulse remained low (approximately 1/2 of baseline) and the subject could not maintain consciousness in a seated position. The subject was reclined and moved to an operating room recovery area where he rested for approximately 1 hour after which the subject's vital signs had returned to pre-exposure values. Subject #3 displayed a rapid rise in blood concentration of HFC-134a which reached 1.29 mg/L at the 2.5 minute point in the exposure (Figure 3). The blood sample scheduled for 3 minutes was not collected. The medical representative had considerable difficulty getting blood from the cannula at the 3-minute point and significant manipulation of the indwelling cannula was noted. No further blood samples were taken. Subject #5 was also exposed to 4000 ppm (0.4% v/v) HFC-134a. There was some difficulty with blood collection and manipulation of the cannula was noted, but exposure was uneventful through the first 10 minutes of exposure. Breathing effort and rate appeared normal. At approximately 10.5 minutes into the exposure the subject's blood pressure and pulse began to rise rapidly and the subject gave the hand signal for possible trouble. His pulse rose rapidly until it was double the pre-exposure value, at which time the subject gave the hand signal to terminate the exposure. The exposure was aborted and the subject began breathing room air, but the in-dwelling cannula was not removed from the subject. After 30 seconds, the subject's blood pressure and pulse were at pre-exposure levels. The HFC-134a concentration in blood reached 0.70 mg/L at the point where the exposure was terminated (Figure 3). Subject #5 breathed room air for 1 hour and was then re-exposed to 2000 ppm (0.2% v/v) HFC-134a. After 2.5 minutes of exposure, the subject's blood pressure and pulse again rose rapidly, the subject signaled trouble and the exposure was terminated. The subject's vital signs returned to pre-exposure levels within 30 seconds after the exposure was terminated. The in-dwelling cannula remained attached to the subject and blood was drawn for an additional 10 minutes at 1-minute intervals. The venous blood concentration of HFC-134a was 0.16 mg/L at the start of the 2000 ppm exposure and reached 0.38 mg/L at the time of exposure termination (Figure 3). The HFC-134a concentration was still at 0.2 mg/L 10 minutes after the exposure was terminated. No further human HFC-134a exposures were conducted. In addition to the monitored effects, there were several subjective effects associated with the inhalation exposures to HFC-134a. Subject #3 reported problems with dizziness and balance following the exposure. At the time of this report (6 weeks post exposure), both the dizziness and balance problems still persisted. Subject #5 reported chest tightness and a headache with associated dizziness immediately following the exposure. The headache subsided by the time the subject woke up the day following the exposure. The day following the exposure, subject #5 reported unusual feelings in the chest resembling "flutters". The chest tightness was reported to subside within 3 days of the exposure and the "flutters" within 2 weeks of the exposure. As with subject #3, subject #5 was still experiencing dizziness and balance problems at the time of this report (6 weeks post exposure). Subject #5 also reported persistent ringing in the ears which was still present at the time of this report. The adverse events observed during the exposures to HFC-134a and HFC-227ea were unexpected and inconsistent with the published data. Based on the published data on HFC-134a and HFC-227ea, no adverse effects should have been observed at the 0.4% v/v and 0.6% levels, respectively, used in this study. Both HFC-134a and HFC-227ea have been considered to be inert compounds which exert toxic effects only after their concentrations are so high that oxygen depravation effects prevail (Graepel and Alexander, 1991)... Rats and mice have shown no acute toxicity during or after a 1-hour inhalation exposure to 810,000 ppm HFC-134a and dogs were essentially unaffected following an 80,000 ppm exposure (Alexander, 1995). Based on the laboratory animal data, Alexander, 1995, concluded that HFA-134a is devoid of acute and long term toxicity, is poorly absorbed and is rapidly excreted. In addition to the claims of inertness, the chemicals of interest have been reported to rapidly leave the human system with an apparent half-life of only 5.1 minutes (Harrison, 1996). Similarly, another report states that only 10% of the administered dose of HFC-134a remained 10 minutes after termination of the exposure (Woodcock, 1995). The 5.1 minute half-life for HFC-134a and extremely rapid elimination is in contrast to the 31 minute apparent half-life reported as part of a clinical pharmacology study (Ventresca, 1995). While the sample size was extremely small in our study due to unplanned termination, the apparent half-lives of HFC-134a and HFC-227ea are estimated to be 12.6 and 7.5 minutes, respectively (Figures 2 and 3). This probably represents only the rapid elimination phase since data were not available to assess any slower elimination phases that may be present. As such, the half-life estimates could be quite low especially since measurable levels of HFC-134a were present 1 hour after the exposure was terminated (Figure 2). The presence of HFC-134a in the blood 1 hour after exposure was unexpected. Alexander, 1995, reported that there was no carry over in blood after 30 minutes. Halon 1301 cleared more rapidly with an estimated half-life of 3.6 minutes. Based on published work, regulatory approval and commercial use of Halon 1301, HFC-134a and HFC-227ea, the exposure levels selected for the 30-minute inhalation exposures were expected to be without adverse effects in humans. Since the study was designed to collect only kinetic information for use in PBPK model validation and only at "no effect" concentration levels, clinical type experimental design was not adopted. Additionally, the subjects participating in the study were scientists or technicians and they were knowledgeable about the study results as they occurred... In summary, all 7 human volunteers completed the Halon 1301 exposures without incident while both the HFC-134a and HFC-227ea exposures were terminated due to the adverse effects described in this report. Additionally, no adverse effects were reported during "blank" exposures where all conditions were the same as in chemical exposures except the test material was air. Based on the chemical similarity between HFC-134a and HFC-227ea and the similar human responses during the exposures, it became the opinion of the investigators that further exposures would constitute a study of human effects rather than simply of kinetics. Given this opinion, the study was terminated. In view of the sample size and experimental design, no conclusion or speculation about cause and effect is offered at this time. Rather, the purpose of this document is to report the unexpected events that occurred during human inhalation of HFC-134a and HFC-227ea under controlled conditions.
Ref: 1997. Human Inhalation of Halon 1301, HFC-134a and HFC-227ea for Collection of Pharmacokinetic Data.
http://www.fluoridealert.org/pesticides/1.1.1.2.3.3.3-Hep.97.REPORT.htm

Body Weight Decrease (click on for all fluorinated pesticides)

-- In a developmental toxicity study, Lu and Staples (1981) exposed pregnant CD rats to HFC-134a at 30,000, 100,000, or 300,000 ppm for 6 h/d from days 6 to 15 of gestation. Following exposure of dams at 300,000 ppm, there was a significant reduction in fetal weight and significant increases in several skeletal variations. At 300,000 ppm, signs of maternal toxicity included reduced food consumption, reduced body weight gain, lack of response to noise stimuli, severe tremors, and uncoordinated movements. Dams exposed at 100,000 ppm showed reduced response to noise stimuli and uncoordinated movements. No terata or evidence for developmental toxicity were observed following exposure of dams at 30,000 or 100,000 ppm.
-- -- Hodge et al. (1979) exposed groups of 29 or 30 pregnant Wistar-derived rats to HFC-134a at 0, 1,000, 10,000, or 50,000 ppm for 6 h/d on days 6 to 15 of gestation. Abnormal clinical signs were observed in the animals, but there was no effect on maternal body weights. At 50,000 ppm, there was no evidence of terata, but fetal body weight was significantly reduced, and skeletal ossification was significantly delayed. There were no effects on any parameter at 10,000 ppm.
-- -- Groups of 28 pregnant New Zealand white rabbits were exposed at 0, 2,500, 10,000, or 40,000 ppm for 6 h/d on days 7 through 19 of pregnancy (Collins et al. 1995; Wickramaratne 1989 a,b). Doe were weighed during the study and sacrificed on day 29 of gestation... In the mid- and high-dose exposure groups, doe had reduced body weight gains compared with the control group; lower weight gains were partially associated with decreased food consumption. With the exception of a significantly increased incidence of unossified seventh-lumbar transverse process in fetuses in the 10,000- and 40,000-ppm groups, all other parameters were similar among control and treatment groups. This effect was also observed in the control group and was not considered treatment related. Therefore, there was no adverse developmental or teratogenic effect associated with exposure to FC-134a.
-- ... Fetotoxicity was ovserved in rats when dams were exposed at 50,000 ppm (Hodge et al. 1979). Slight maternal toxicity in rabbits, as indicated by lower body weight gains compared with the control group, were noted at 10,000 and 50,000 ppm (Collins et al. 1995). There was a slight delay in physical development of F1 rats following exposure of F0 females at 64,400 ppm (Alexander et al. 1996).
-- Alexander DJ, Libretto SE, Adams MJ, Hughes EW, Bannerman M. 1996. HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats. Human Exp Toxicol 15:508-517.
-- Collins MA, Rusch GM, Sato F, Hext PM, Millischer RJ. 1995. 1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl Toxicol 25:271-280.
-- Hodge MCE, Kilmartin M, Riley RA, Weight TM, Wilson J. 1979. Arcton 134a: teratogenicity study in the rat. ICI Report no. CTL/P/417. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, U.K.
Lu M, Staples R. 1981. 1,1,1,2-tetrafkyirietgabe (FC-134a): embryo-fetal toxicity and teratogenicity study by inhalation in the rat. Report No. 317-81. Haskell Laboratory, Wilmington, DE.
-- Wickramaratne GA. 1989a. HCF-134a: Teratogenicity inhalation study in the rabbit. ICI Report No. CTL/P/2504. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire UK (Unpublished).
-- Wickramaratne GA. 1989b. HCF-134a: Embryotoxicity inhalation study in the rabbit. ICI Report No. CTL/P/2380. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, UK. (Unpublished).
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html

Bone (click on for all fluorinated pesticides)

-- In a developmental toxicity study, Lu and Staples (1981) exposed pregnant CD rats to HFC-134a at 30,000, 100,000, or 300,000 ppm for 6 h/d from days 6 to 15 of gestation. Following exposure of dams at 300,000 ppm, there was a significant reduction in fetal weight and significant increases in several skeletal variations. At 300,000 ppm, signs of maternal toxicity included reduced food consumption, reduced body weight gain, lack of response to noise stimuli, severe tremors, and uncoordinated movements. Dams exposed at 100,000 ppm showed reduced response to noise stimuli and uncoordinated movements. No terata or evidence for developmental toxicity were observed following exposure of dams at 30,000 or 100,000 ppm.
-- Hodge et al. (1979) exposed groups of 29 or 30 pregnant Wistar-derived rats to HFC-134a at 0, 1,000, 10,000, or 50,000 ppm for 6 h/d on days 6 to 15 of gestation. Abnormal clinical signs were observed in the animals, but there was no effect on maternal body weights. At 50,000 ppm, there was no evidence of terata, but fetal body weight was significantly reduced, and skeletal ossification was significantly delayed. There were no effects on any parameter at 10,000 ppm.
-- Groups of 28 pregnant New Zealand white rabbits were exposed at 0, 2,500, 10,000, or 40,000 ppm for 6 h/d on days 7 through 19 of pregnancy (Collins et al. 1995; Wickramaratne 1989 a,b). Doe were weighed during the study and sacrificed on day 29 of gestation... In the mid- and high-dose exposure groups, doe had reduced body weight gains compared with the control group; lower weight gains were partially associated with decreased food consumption. With the exception of a significantly increased incidence of unossified seventh-lumbar transverse process in fetuses in the 10,000- and 40,000-ppm groups, all other parameters were similar among control and treatment groups. This effect was also observed in the control group and was not considered treatment related. Therefore, there was no adverse developmental or teratogenic effect associated with exposure to FC-134a.
-- -- ... Fetotoxicity was ovserved in rats when dams were exposed at 50,000 ppm (Hodge et al. 1979). Slight maternal toxicity in rabbits, as indicated by lower body weight gains compared with the control group, were noted at 10,000 and 50,000 ppm (Collins et al. 1995). There was a slight delay in physical development of F1 rats following exposure of F0 females at 64,400 ppm (Alexander et al. 1996).
-- Alexander DJ, Libretto SE, Adams MJ, Hughes EW, Bannerman M. 1996. HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats. Human Exp Toxicol 15:508-517.
-- Collins MA, Rusch GM, Sato F, Hext PM, Millischer RJ. 1995. 1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl Toxicol 25:271-280.
-- Hodge MCE, Kilmartin M, Riley RA, Weight TM, Wilson J. 1979. Arcton 134a: teratogenicity study in the rat. ICI Report no. CTL/P/417. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, U.K.
-- Lu M, Staples R. 1981. 1,1,1,2-tetrafkyirietgabe (FC-134a): embryo-fetal toxicity and teratogenicity study by inhalation in the rat. Report No. 317-81. Haskell Laboratory, Wilmington, DE. (Cited in NRC 1996).
-- Wickramaratne GA. 1989a. HCF-134a: Teratogenicity inhalation study in the rabbit. ICI Report No. CTL/P/2504. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire UK (Unpublished).
-- Wickramaratne GA. 1989b. HCF-134a: Embryotoxicity inhalation study in the rabbit. ICI Report No. CTL/P/2380. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, UK. (Unpublished).
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html

MUSCULOSKELETAL 0.2.15.1 ACUTE EXPOSURE - Rhabdomyolysis has been reported in a worker susceptible to malignant hyperthermia after exposure to fluorinated hydrocarbons and also following intentional freon inhalation. Compartment syndrome is a rare complication of severe exposure.
Ref: Hazardous Substances Data Bank for 1,1,1,2-TETRAFLUOROETHANE CASRN: 811-97-2.
http://www.fluorideaction.org/pesticides/1,1,1,2-tetrafluoroe.toxnet.htm

• Note from FAN: From online site on Rhabdomyolysis by DR PAUL A. BAGGALEY -----
Rhabdomyolysis is a common disorder which may result from a large variety of diseases, trauma, or toxic insults to skeletal muscle. It may be defined as a clinical and biochemical syndrome resulting from an injury which damages the integrity of the sarcolemma of skeletal muscle, leading to the release of potentially toxic muscle cell components into the circulation.(1,2,3) This may result in potential life-threatening complications including myoglobinuric acute renal failure, hyperkalaemia and cardiac arrest, disseminated intravascular coagulation, and more locally, compartment syndrome.
http://members.tripod.com/~baggas/rhabdo.html

Brain and CNS (click on for all fluorinated pesticides)

-- NEUROLOGIC 0.2.7.1. ACUTE EXPOSURE - Headache, dizziness, and disorientation are common. Cerebral edema may be found on autopsy. A syndrome of impaired psychomotor speed, impaired memory and learning, and emotional lability has been described in workers with chronic occupational exposure to fluorinated hydrocarbons.
-- THERE IS A SIGNIFICANT ACCUMULATION OF FLUOROCARBONS IN BRAIN, LIVER & LUNG COMPARED TO BLOOD LEVELS, SIGNIFYING A TISSUE DISTRIBUTION OF FLUOROCARBONS SIMILAR TO THAT OF CHLOROFORM. /FLUOROCARBONS/ [Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3076]
Ref: Hazardous Substances Data Bank for 1,1,1,2-TETRAFLUOROETHANE CASRN: 811-97-2.
http://www.fluorideaction.org/pesticides/1,1,1,2-tetrafluoroe.toxnet.htm

Endocrine: Testicular (click on for all fluorinated pesticides)

-- groups of 16 male and 16 female rats were exposed at concentrations of 9, 1000, 10,000, or 50,000 ppm 6 h/d for 20 d of a 28-d period (Riley et al. 1979). No treatment-related effects were observed with regard to body weight, clinical signs, hematology, blood chemistry, urine composition, or ophthalmoscopy. Changes in liver, kidney, and gonad weights of male rats in the group exposed to 50,000 ppm were noted with a significant increase in liver weight in the 10,000-ppm group also. In the absence of pathological changes in these organs, Riley et al. (1979) considered these changes physiological adaptations to treatment.
-- 3.4 Developmental and Reproductive Toxicity (pages 134 - 136)
-- In a 28-d study conducted by Riley et al. (1979), 16 male rats were exposed to HFC-134a at 0, 1,000, 10,000, or 50,000 ppm 6 h/d, 5 d/wk. Rats exposed at 50,000 ppm exhibited decreased testicular weights. However, in a 13-wk study, no effects on testicular weight were evident (see Section 3.7) (Hext 1989; Collins et al. 1995). In the chronic study (see Section 3.7) (Collins et al. 1995), Leydig (interstitial) cell hyperplasia and benign Leydig cell tumors were reported following exposure at 50,000 ppm for 104 wk; no such effects were reported following exposure for 104 wk at 10,000 ppm. However, it should be noted that these findings are not relevant for humans because the rat is prone to developing these types of tumors spontaneously.
-- 3.7 Subchronic and Chronic Toxicity and Carcinogenicity (pages 138 - 139)
-- groups of 85 male and 85 female rats were exposed to concentrations at 0, 2,500, 10,000, or 50,000 ppm for 6 h/d, 5 d/wk for 104 wk (Collins et al. 1995). Exposure conditions and analytical measurements were identical to procedures followed in the 13 week study. Ten animals from each group were sacrificed at 52 wk. At 52 and 104 wk there were no effects on clinical condition, food consumption, growth, survival, hematology, clinical chemistry, or urinary parameters. Absolute liver weights of females were increased in the groups exposed at 2,500 and 50,000 ppm but not in the group exposed at 10,000 ppm. Males in groups that received 10,000 or 50,000 ppm for 104 wk had an increased incidence of enlarges testes (not statistically significant), and males in the group that received 50,000 ppm for 104 wk had a statistically significant increase in incidence of Leydig cell hyperplasia (40 vs. 27 in the concurrent control group) and Leydig cell adenomas (23 vs. 9 in the concurrent control group). There was no evidence of progression to malignancy. As discussed earlier, these tumors are not relevant to humans.
-- Although there was an increased incidence of testicular Leydig cell adenomas in male rats administered 50,000 ppm for 104 wk (Collins et al. 1995), these tumors do not progress to malignancy (Boorman et al. 1990) and have little significance in humans (Cook et al. 1999)...
-- Boorman GA, Eustis SL, Elwell MR. 1990. Pathology of the Fischer Rat: Reference and Atlas. New York Academic Press, Inc.
-- Riley RA, Bennett IP, Chart IS, Gore CW, Robinson M, Weight TM. 1979. Arcton-134a: Subacute toxicity to the rat by inhalation. ICI Report No. CTL/P/463. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, UK.
-- Collins MA, Rusch GM, Sato F, Hext PM, Millischer RJ. 1995. 1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl Toxicol 25:271-280.
-- Cook JC, Klinefelter GR, Hardisty JF, Sharpe RM, Foster PMD. 1999. Rodent Leydig cell tumorigenesis: a review of the physiology, pathology, mechanisms, and relevance to humans. Crit Rev Toxicol 29:169-261.
-- Hext PM. 1989. 90-day inhalation toxicity study in the rat. ICI Report No. CTL/P/2466. Central Toxicology Laboratory, Imperial Chemical Industries, Alderley Park, Macclesfield, Cheshire, U.K. (Cited in NRC 1996).
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X . Online at:
http://books.nap.edu/books/030908511X/html/index.html

Eye (click on for all fluorinated pesticides)

-- In the perinatal and postnatal part of the study, groups of 41 female rats were administered concentrations of 1,800, 9,900, or 64,400 ppm of HFC-134a (99.3% pure) for 1 h daily during days 17 to 20 of pregnancy and days 1 to 21 postpartum (Alexander et al. 1996). Females were allowed to deliver and rear their young. Selected F1 animals were mated; these animals were sacrified on day 20 of pregnancy, and the uterine contents were examed... There was a statistically significant delay in the occurrence of pinnae detatchment, eye-opening, and startle response in the F1 generation, whose dams inhaled 64,400 ppm....
-- Alexander DJ, Libretto SE, Adams MJ, Hughes EW, Bannerman M. 1996. HFA-134a (1,1,1,2-tetrafluoroethane): effects of inhalation exposure upon reproductive performance, development and maturation of rats. Human Exp Toxicol 15:508-517.
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html

Heart (click on for all fluorinated pesticides)

4.2 Mechanism of Toxicity (pages 143 - 144)
At high concentrations, HFC-134a has anesthetic and narcotic properties; cardiac sensitization may also occur. The biochemical mechanism(s) of action of these two efects is not well understood. The anesthetic effect was fully reversible. Inhalation of certain hydrocarbons, including some anesthetics, can make the mammalian heart abnormally sensitive to epinephrine, resulting in ventricular arrhythmias, which is some cases can lead to sudden death (Reinhardt et al. 1971). The mechanism of action of cardiac sensitization is not completely understood but appears to involve a disturbance in the normal conduction of the electrical impulse through the heart, probably by producing a local disturbance in the electrical potential across cell membranes. The hydrocarbons themselves do not produce arrhythmia; the arrhythmia is the result of the potentiation of endogenous epinephrine (adrenalin) by the hydrocarbon ... In the study with human volunteers exposed to HFC-134a (Emmen and Hoogendijk 1998), the relationship between exposure concentration and blood level was linear, and at all exposure concentrations (1,000, 2,000, 4,000, and 8,000 ppm), blood concentrations approached equilibrium at 55 min. Cardiac sensitization is considered a concentration threshold phenomenon (page 146).
-- Emmen HH, Hoogendijk EMG. 1998. Report on an ascending dose safety study comparing HFA-13a with CFC-12 and air, administered by whole-body exposure to healthy volunteers. MA-250B-82-306, TNO Report V98.754, The Netherlands Organization Nutrition and Food Research Institute, Zeist, The Netherlands.
-- Reinhardt CF, Azar A, Maxfield ME, Smith PE, Mullin LS. 1971. Cardiac arrhythmias and aerosol "sniffing." Arch Environ Health 22:265-279.
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html

Subject #3 was the first volunteer exposed to HFC-134a. The exposure concentration was 4000 ppm (0.4% v/v) and was scheduled to last for 30 minutes with a 5-minute postexposure evaluation period as was accomplished in the Halon 1301 portion of the study. Approximately 4.5 minutes into the exposure, the subject lost consciousness and both pulse and blood pressure dropped to zero. The exposure was immediately aborted and the subject was removed from the exposure apparatus. Medical personnel intervened and after pulse and blood pressure were restored the subject was administered 100% oxygen. Blood pressure and pulse remained low (approximately 1/2 of baseline) and the subject could not maintain consciousness in a seated position. The subject was reclined and moved to an operating room recovery area where he rested for approximately 1 hour after which the subject's vital signs had returned to pre-exposure values... Subject #5 was also exposed to 4000 ppm (0.4% v/v) HFC-134a. There was some difficulty with blood collection and manipulation of the cannula was noted, but exposure was uneventful through the first 10 minutes of exposure. Breathing effort and rate appeared normal. At approximately 10.5 minutes into the exposure the subject's blood pressure and pulse began to rise rapidly and the subject gave the hand signal for possible trouble. His pulse rose rapidly until it was double the pre-exposure value, at which time the subject gave the hand signal to terminate the exposure. The exposure was aborted and the subject began breathing room air, but the in-dwelling cannula was not removed from the subject. After 30 seconds, the subject's blood pressure and pulse were at pre-exposure levels. The HFC-134a concentration in blood reached 0.70 mg/L at the point where the exposure was terminated (Figure 3). Subject #5 breathed room air for 1 hour and was then re-exposed to 2000 ppm (0.2% v/v) HFC-134a. After 2.5 minutes of exposure, the subject's blood pressure and pulse again rose rapidly, the subject signaled trouble and the exposure was terminated. The subject's vital signs returned to pre-exposure levels within 30 seconds after the exposure was terminated... No further human HFC-134a exposures were conducted. In addition to the monitored effects, there were several subjective effects associated with the inhalation exposures to HFC-134a. Subject #3 reported problems with dizziness and balance following the exposure. At the time of this report (6 weeks post exposure), both the dizziness and balance problems still persisted. Subject #5 reported chest tightness and a headache with associated dizziness immediately following the exposure. The headache subsided by the time the subject woke up the day following the exposure. The day following the exposure, subject #5 reported unusual feelings in the chest resembling "flutters". The chest tightness was reported to subside within 3 days of the exposure and the "flutters" within 2 weeks of the exposure. As with subject #3, subject #5 was still experiencing dizziness and balance problems at the time of this report (6 weeks post exposure). Subject #5 also reported persistent ringing in the ears which was still present at the time of this report. The adverse events observed during the exposures to HFC-134a and HFC-227ea were unexpected and inconsistent with the published data... Based on published work, regulatory approval and commercial use of Halon 1301, HFC-134a and HFC-227ea, the exposure levels selected for the 30-minute inhalation exposures were expected to be without adverse effects in humans.
Ref: 1997. Human Inhalation of Halon 1301, HFC-134a and HFC-227ea for Collection of Pharmacokinetic Data.
http://www.fluoridealert.org/pesticides/1.1.1.2.3.3.3-Hep.97.REPORT.htm

Kidney (click on for all fluorinated pesticides)

Comparative potency studies showed that 1,1,1,2-tetrafluoroethane, dichlorodifluoromethane, or 1,1,2,2-tetrafluoro-1,2-dichloroethane (25% gas phase) inhibited gluconeogenesis about equally while as little as 300 ppm halothane was effective and 1,1,1,2,2-pentafluoro-2-chloroethane (25%) was without effect. Considering that the threshold for alteration of the rate of glucose metabolism in this in vitro paradigm is about 12.5% 1,1,1,2-tetrafluoroethane, it was concluded that toxicologically significant alteration of glucose-linked bioenergetics is unlikely at the levels of 1,1,1,2-tetrafluoroethane exposure anticipated in workplace or environment. [Olson MJ et al; Fundam Appl Toxicol 15 (2): 270-80 (1990)]
Ref: Hazardous Substances Data Bank for 1,1,1,2-TETRAFLUOROETHANE CASRN: 811-97-2.
http://www.fluorideaction.org/pesticides/1,1,1,2-tetrafluoroe.toxnet.htm

Note from FAN:
Definition Gluconeogenesis: The process of making glucose (sugar) from its own breakdown products or from the breakdown products of lipids (fats) or proteins. Gluconeogenesis occurs mainly in cells of the liver or kidney.

-- groups of 16 male and 16 female rats were exposed at concentrations of 9, 1000, 10,000, or 50,000 ppm 6 h/d for 20 d of a 28-d period (Riley et al. 1979). No treatment-related effects were observed with regard to body weight, clinical signs, hematology, blood chemistry, urine composition, or ophthalmoscopy. Changes in liver, kidney, and gonad weights of male rats in the group exposed to 50,000 ppm were noted with a significant increase in liver weight in the 10,000-ppm group also. In the absence of pathological changes in these organs, Riley et al. (1979) considered these changes physiological adaptations to treatment.
-- Riley RA, Bennett IP, Chart IS, Gore CW, Robinson M, Weight TM. 1979. Arcton-134a: Subacute toxicity to the rat by inhalation. ICI Report No. CTL/P/463. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, UK.
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html

Liver (click on for all fluorinated pesticides)

Comparative potency studies showed that 1,1,1,2-tetrafluoroethane, dichlorodifluoromethane, or 1,1,2,2-tetrafluoro-1,2-dichloroethane (25% gas phase) inhibited gluconeogenesis about equally while as little as 300 ppm halothane was effective and 1,1,1,2,2-pentafluoro-2-chloroethane (25%) was without effect. Considering that the threshold for alteration of the rate of glucose metabolism in this in vitro paradigm is about 12.5% 1,1,1,2-tetrafluoroethane, it was concluded that toxicologically significant alteration of glucose-linked bioenergetics is unlikely at the levels of 1,1,1,2-tetrafluoroethane exposure anticipated in workplace or environment. [Olson MJ et al; Fundam Appl Toxicol 15 (2): 270-80 (1990)]
Note from FAN: Definition Gluconeogenesis: The process of making glucose (sugar) from its own breakdown products or from the breakdown products of lipids (fats) or proteins. Gluconeogenesis occurs mainly in cells of the liver or kidney.
Ref: Hazardous Substances Data Bank for 1,1,1,2-TETRAFLUOROETHANE CASRN: 811-97-2.
http://www.fluorideaction.org/pesticides/1,1,1,2-tetrafluoroe.toxnet.htm

-- groups of 16 male and 16 female rats were exposed at concentrations of 9, 1000, 10,000, or 50,000 ppm 6 h/d for 20 d of a 28-d period (Riley et al. 1979). No treatment-related effects were observed with regard to body weight, clinical signs, hematology, blood chemistry, urine composition, or ophthalmoscopy. Changes in liver, kidney, and gonad weights of male rats in the group exposed to 50,000 ppm were noted with a significant increase in liver weight in the 10,000-ppm group also. In the absence of pathological changes in these organs, Riley et al. (1979) considered these changes physiological adaptations to treatment.
-- 3.7 Subchronic and Chronic Toxicity and Carcinogenicity (pages 138 - 139)
... groups of 85 male and 85 female rats were exposed to concentrations at 0, 2,500, 10,000, or 50,000 ppm for 6 h/d, 5 d/wk for 104 wk (Collins et al. 1995). Exposure conditions and analytical measurements were identical to procedures followed in the 13 week study. Ten animals from each group were sacrificed at 52 wk. At 52 and 104 wk there were no effects on clinical condition, food consumption, growth, survival, hematology, clinical chemistry, or urinary parameters. Absolute liver weights of females were increased in the groups exposed at 2,500 and 50,000 ppm but not in the group exposed at 10,000 ppm. Males in groups that received 10,000 or 50,000 ppm for 104 wk had an increased incidence of enlarges testes (not statistically significant), and males in the group that received 50,000 ppm for 104 wk had a statistically significant increase in incidence of Leydig cell hyperplasia (40 vs. 27 in the concurrent control group) and Leydig cell adenomas (23 vs. 9 in the concurrent control group). There was no evidence of progression to malignancy. As discussed earlier, these tumors are not relevant to humans.
-- Collins MA, Rusch GM, Sato F, Hext PM, Millischer RJ. 1995. 1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl Toxicol 25:271-280.
-- Riley RA, Bennett IP, Chart IS, Gore CW, Robinson M, Weight TM. 1979. Arcton-134a: Subacute toxicity to the rat by inhalation. ICI Report No. CTL/P/463. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, UK.
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html

Lung (click on for all fluorinated pesticides)

3.2.3 Rats (pages 131 - 132). Groups of ten male rats were exposed at concentrations of 0, 10,000, 50,000, or 100,000 ppm for 6 h/d, 5 d/wk for 2 wk (Silber and Kenedy 1979b). Five rats from each group were sacrificed at the end of the tenth exposure, and the remaining fie rats per group were sacrificed after a 14-d recovery period. No treatment-related changes in weight gain, hematology parameters, blood chemistry, or organ weights were observed. Increased incidence of focal interstitial pneumonitis of the lung was the only adverse effect observed in the groups exposed at 50,000 and 100,000 ppm. The fluoride content of the urine was significantly increased in the treated rats.
-- Silber LS, Kennedy GL. 1979b. Subacute inhalation toxicity of tetrafluoroethane (FC 134a). Haskell Laboratory, Report No. 422-79, DuPont de Nemours and Company, Newark DE, cited in ECETOC, 1995.
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html

Ringing in Ears (click on for all fluorinated pesticides)

-- The adverse events observed during the exposures to HFC-134a and HFC-227ea were unexpected and inconsistent with the published data. Based on the published data on HFC-134a and HFC-227ea, no adverse effects should have been observed at the 0.4% v/v and 0.6% levels, respectively, used in this study.
-- Subject #3 reported problems with dizziness and balance following the exposure. At the time of this report (6 weeks post exposure), both the dizziness and balance problems still persisted. Subject #5 reported chest tightness and a headache with associated dizziness immediately following the exposure. The headache subsided by the time the subject woke up the day following the exposure. The day following the exposure, subject #5 reported unusual feelings in the chest resembling "flutters". The chest tightness was reported to subside within 3 days of the exposure and the "flutters" within 2 weeks of the exposure. As with subject #3, subject #5 was still experiencing dizziness and balance problems at the time of this report (6 weeks post exposure). Subject #5 also reported persistent ringing in the ears which was still present at the time of this report.
-- The presence of HFC-134a in the blood 1 hour after exposure was unexpected.
-- In summary, all 7 human volunteers completed the Halon 1301 exposures without incident while both the HFC-134a and HFC-227ea exposures were terminated due to the adverse effects described in this report.
Ref: 1997. Human Inhalation of Halon 1301, HFC-134a and HFC-227ea for Collection of Pharmacokinetic Data. 19 Aug 97.
http://www.fluoridealert.org/pesticides/1.1.1.2.3.3.3-Hep.97.REPORT.htm

Tremors (click on for all fluorinated pesticides)

-- In a developmental toxicity study, Lu and Staples (1981) exposed pregnant CD rats to HFC-134a at 30,000, 100,000, or 300,000 ppm for 6 h/d from days 6 to 15 of gestation. Following exposure of dams at 300,000 ppm, there was a significant reduction in fetal weight and significant increases in several skeletal variations. At 300,000 ppm, signs of maternal toxicity included reduced food consumption, reduced body weight gain, lack of response to noise stimuli, severe tremors, and uncoordinated movements. Dams exposed at 100,000 ppm showed reduced response to noise stimuli and uncoordinated movements. No terata or evidence for developmental toxicity were observed following exposure of dams at 30,000 or 100,000 ppm.
-- Lu M, Staples R. 1981. 1,1,1,2-tetrafkyirietgabe (FC-134a): embryo-fetal toxicity and teratogenicity study by inhalation in the rat. Report No. 317-81. Haskell Laboratory, Wilmington, DE.
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels, Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:
http://books.nap.edu/books/030908511X/html/index.html