Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 2 (2002) / Chapter Skim
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Appendix 3: 1,1,1,2-Tetrafluoroethane (HFC-134A)
Appendix 3: 1,1,1,2-Tetrafluoroethane (HFC-134A)
Pages 120-165
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on Acute Exposure Guideline Levels for Hazardous Substances, including George Rusch (Chemical Manager) and Robert Benson and Kenneth Still (Chemical Reviewers)
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of 1 was applied. The intraspecies UP of ~ is supported by the absence of adverse effects in therapy tests with patients with severe chronic obstructive pulmonary disease and adult and pediatric asthmatics who were tested with metered-dose inhalers containing HFC-134a as the propellant.
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for the human heart, an interspecies UF of ~ was applied. Because the cardiac sensitization test is highly sensitive as the response to exogenous epinephrine is optimized, an intraspecies UF of 3 was applied to account for sensitive individuals.
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Response to challenge dose of epinephrine (cardiac sensitization test)
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were located. Animal studies addressed neurotoxicity, genotoxicity, carcinogenicity, and cardiac sensitization and were conducted over acute, subchronic, and chronic exposure durations.
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Atmospheres were within a few percent of nominal concentrations; the mean oxygen concentration was approximately 20.5%. No significant or consistent differences were found between air exposure and test chemical exposure for clinical observations, blood pressure, heart rate, peak expiratory flow, or EKG recordings.
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When radiolabeled HFC-134a was delivered by metered dose inhalers to healthy subjects and patients with severe chronic obstructive pulmonary disease (COPD) , there were no adverse effects in either group as monitored by vital signs, pulmonary function tests, EKG, and liver function.
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The therapeutic agent was equally protective against methacholine challenge regardless of propellant. In a similar study with 24 male and female asthmatic patients (mean age, 37 y)
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2.7. Summary In a study with human volunteers exposed at concentrations up to 8,000 ppm for ~ h, no adverse effects on pulmonary function, clinical chemistry, hematology parameters, or heart rate or rhythm were observed.
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Two of six rats exposed at 652,700 ppm also died. No deaths were recorded following exposure to the three lower concentrations, and no adverse effects were reported at the concentration of ~ ~ ,000 ppm.
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, there was no effect of the HFC-134a on the salbutamol treatment compared with other CFC propellants. HFC-134a added to the formulation had no influence on histamine-induced bronchoconstriction, blood pressure, or heart rate in the anesthetized dogs.
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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.
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discharge 2001 300,000 < 2 min Narcosis Rat 280,000 10 min Loss of righting Collins 1984 reflex Rat 81,100 4 h No effect Silber and Ken 205,200 4 h Lethargy, rapid res- nedy 1979a piration 359,300 4 h Lethargy, rapid res piration, trembling, tearing Mouse 270,000 - EC50: loss of right- Shulman and ing reflex Sadove 1967 500,000 ~ 30 s Narcosis regard to body weight, clinical signs, hematology, blood chemistry, urine composition, or ophthalmoscopy. Changes in liver, kidney, and gonad weights of mate rats in the group exposed at 50,000 ppm were noted with a significant increase in liver weight in the 1 O,000-ppm group also.
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At 140,000 ppm, food rewards earned were significantly reduced, although the error-to-reward ratios were significantly increased.
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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.
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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- and40,000-ppmgroups, all other parameters were similar among control and treatment groups.
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Two of ten dogs exhibited multiple ventncular beats during exposures at 75,000 ppm, and two of four dogs showed marked responses at 100,000 ppm; one dog developed multiple consecutive ventricular beats, and one dog was afflicted with ventricular fibrillation leading to cardiac arrest. Hardy et al.
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Because the administration of exogenous epinephrine results in an increase in circulating epinephrine concentration—up to ten times the physiological level in stressed animals (Chengelis ~ 997) the results ofthe cardiac sensitization protocol are considered to represent a highly sensitive measurement.
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Survival, clinical condition, growth, and a variety of hematological, clinical chemistry, and urinary parameters were monitored. During the exposures there were no treatment-related clinical signs.
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There were no effects on survival, clinical signs, behavior (neurotoxicity) , body weights, hematology or on the type, incidence, site, or severity of gross or microscopic lesions or neoplasms.
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Blood concentrations fall rapidly following cessation of exposure as the parent compound is exhaled unchanged. Rapid elimination is typical of poorly soluble materials with high vapor pressures and demonstrates a lack of potential to bioaccumulate (Ernmen et al.
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The elimination half-lives at the respective concentrations were at 10.24, 12.69, 12.26, and 9.77 min in males and 11.36, 14.01, 13.20, and 16.69 min in females. Absorption of ~8F-radiolabeled HFC-134a delivered by metered-dose inhalers via a single breath to seven healthy mate subjects was rapid, and maximum blood concentrations of approximately I.l and I.3 ,ug/mL were attained within 30-60 s (Pike et al.
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Following exposure of both mate and female rats for 1 h daily for ~ 10 wk. blood concentrations in the 2,500-, 10,000-, and 50,000-ppm groups were 4.24.5, 16.5, and 62.3 ,ug/mE, respectively (Alexander et al.
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Although other species have been tested, the dog is the species of choice for the mammalian cardiac sensitization model because the dog is a reliable cardiovascular model for humans, has a large heart size, and can be trained to calmly accept the experimental procedures (Aviado 1994; NRC 1996~. The cardiac sensitization test was evaluated by NRC (1996)
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Although this test is useful for identifying compounds capable of cardiac sensitization, the capacity to establish an effect level is limited. The test is very conservative as the levels of epinephrine administered represent an approximate lO-fold excess over blood concentrations that would be achieved endogenously in dogs (Chengelis 1997)
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LCso values for the rat at 15 min and 4 h were several hundred thousand parts per million (Table 3-3~. Time scaling may not be relevant for halogenated hydrocarbons as blood concentrations of these chemicals do not increase as exposure time increases
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, the relationship between exposure concentration and blood level was linear, and at all exposure concentrations (l,000, 2,000, 4,000, and 8,000 ppm) , blood concentrations approached equilibrium at 55 min.
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The parent compound is present in blood; HFC-1 34a is poorly absorbed and poorly metabolized by body tissues and organs. Because the pharmacokinetic data for humans show that blood concentrations do not increase greatly with time after 55 min.
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6.2. Summary of Animal Data Relevant to AEGL-2 Humans exposed to some halogenated hydrocarbons at high concentrations may develop cardiac arrhythmias, which are potentially fatal.
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Because this is a conservative test, an intraspecies UF of 3 was applied to protect potentially susceptible individuals. Blood concentrations were close to equilibrium within 55 min during human exposures, and concentrations of halocarbons that do not produce a positive response in the short-term cardiac sensitization test do not produce the response when exposures are continued for 6 h, so the value of ~ 3,000 ppm (]
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Because the cardiac sensitization test is a conservative test, the 80,000 ppm concentration was adjusted by an intraspecies UF of 3 to protect potentially susceptible individuals. Blood concentrations were close to equi
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Blood concentrations rapidly reach equilibrium, and the blood concentration determines the effect, so the ~ 3,000 ppm value was used across all time periods. The AEGL-3 was based on the lowest response that induced a marked cardiac effect in the cardiac sensitization test with the dog.
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The animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The metabolism of HFC-134a is well understood, and the relationship of exposure con
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9. REFERENCES AIHA (American Industrial Hygiene Association)
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1995. Acute safety of the CFC-free propellant HFA134a from a pressurized metered dose inhaler.
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1991. CFC replacements: safety testing, approval for use in metered dose inhalers.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1994. An alternative metered dose inhaler propellant GR106642X: comparison to chlorofluorocarbon 11 and 12 in the attenuation of histamine-induced bronchoconstriction by salbutamol.
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CTL/P/2380. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, U.K.
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Appendix
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Effects such as cardiac sensitization have been correlated with blood concentrations. Several studies have shown that blood concentrations of halocarbons do not increase greatly with time after 15 min of exposure.
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Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. The values are supported by a study with rats in which no effects were observed during a 4-h exposure to 81,000 ppm.
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Epinephrine is administered prior to and during test exposures at doses that are up to ten times higher than levels secreted by the human adrenal gland in time of stress. Doses of epinephrine were adjusted for each individual dog so that administration of epinephrine without the test chemical produced a threshold response.
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Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. Other effects in animal studies occurred at much higher concentrations or with repeated exposures; the latter are not relevant for setting short-term exposures.
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Epinephrine is administered prior to and during test exposures at doses that are up to ten times higher than levels secreted by the human adrenal gland in time of stress. Doses of epinephrine were adjusted for each individual dog so that administration of epinephrine without the test chemical produced a threshold response.
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Animal studies covered acute, subchronic, and chronic exposure durations and addressed systemic toxicity as well as neurotoxicity, reproductive and developmental effects, cardiac sensitization, genotoxicity, and carcinogenicity. Other effects in animal studies occurred at much higher concentrations or with repeated exposures; the latter are not relevant for setting short-term exposures.
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