The development of environmentally acceptable fluorocarbons

The Nonclinical Assessment of Trans-1,3,3,3-tetrafluoropropene (HFO-1234ze (E)), a Near Zero Global Warming Potential Propellant for Use in Metered Dose Inhalation Products

“…24 Myocardial findings similar to those observed with HFO-1234ze have been reported in Sprague Dawley rats exposed to other HFCs such as HFC-245fa and HCFO-1233zd. 25 However, there were no HFO-1234ze related findings in the heart of dogs in the 39-week study or in the 13-week study in CD1 mice (for which this is also a common background finding) at any dose tested; it is important to note that the highest dose in the 13-week mouse study was 2.4-fold higher than in the 26-week rat study (29,000 mg/kg/day vs 12,000 mg/kg/day). While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf.…”

“…While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf. 25 The lack of cardiac findings in mice, dogs, and minipigs strongly suggests that the rat may be uniquely sensitive to the development of structural cardiac lesions such as RPCM following exposure to very high HFC doses; the effect dose in the 6 month rat study (12,000 mg/kg/day) is approximately more than 3000-fold higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOAEL (4280 mg/kg/day) and associated with a margin of approximately 1000 times (see section on Exposure and Margins of Safety).…”

“…These findings are consistent with the unexpected mortality of some lactating F0 and F1 rats in inhalation 2-generation rat studies with HFC-245fa 26 and HCFO-1233zd. 25 The underlying mechanism to explain the particular sensitivity of lactating rats to HFC exposure is not fully understood. Lactating females exposed to HFO-1234ze or HFC-245fa showed histopathology findings in the CNS characterized by neuronal necrosis, swelling of astrocytes, vacuolation of the neuropil, hemorrhage, and gliosis.…”

“…The nature of these histopathology findings are consistent with those observed following dosing with chemicals associated with so called acute "energy deprivation" syndromes, 27 or impaired energy metabolism. 25,28 Energy deprivation was cited as the likely cause of the CNS lesions in lactating rats exposed to HFC-245fa 26 and would support energy deprivation being the significant contributor to the CNS findings noted in lactating rats exposed to HFO-1234ze. The dose associated with these effects (23,000 mg/kg/ day) is approximately 6000 times higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOEL (5763 mg/kg/day) and associated with a margin of approximately 1500 times (see section on Exposure and Margins of Safety).…”

The Nonclinical Assessment of Trans-1,3,3,3-tetrafluoropropene (HFO-1234ze (E)), a Near Zero Global Warming Potential Propellant for Use in Metered Dose Inhalation Products

“…24 Myocardial findings similar to those observed with HFO-1234ze have been reported in Sprague Dawley rats exposed to other HFCs such as HFC-245fa and HCFO-1233zd. 25 However, there were no HFO-1234ze related findings in the heart of dogs in the 39-week study or in the 13-week study in CD1 mice (for which this is also a common background finding) at any dose tested; it is important to note that the highest dose in the 13-week mouse study was 2.4-fold higher than in the 26-week rat study (29,000 mg/kg/day vs 12,000 mg/kg/day). While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf.…”

“…While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf. 25 The lack of cardiac findings in mice, dogs, and minipigs strongly suggests that the rat may be uniquely sensitive to the development of structural cardiac lesions such as RPCM following exposure to very high HFC doses; the effect dose in the 6 month rat study (12,000 mg/kg/day) is approximately more than 3000-fold higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOAEL (4280 mg/kg/day) and associated with a margin of approximately 1000 times (see section on Exposure and Margins of Safety).…”

“…These findings are consistent with the unexpected mortality of some lactating F0 and F1 rats in inhalation 2-generation rat studies with HFC-245fa 26 and HCFO-1233zd. 25 The underlying mechanism to explain the particular sensitivity of lactating rats to HFC exposure is not fully understood. Lactating females exposed to HFO-1234ze or HFC-245fa showed histopathology findings in the CNS characterized by neuronal necrosis, swelling of astrocytes, vacuolation of the neuropil, hemorrhage, and gliosis.…”

“…The nature of these histopathology findings are consistent with those observed following dosing with chemicals associated with so called acute "energy deprivation" syndromes, 27 or impaired energy metabolism. 25,28 Energy deprivation was cited as the likely cause of the CNS lesions in lactating rats exposed to HFC-245fa 26 and would support energy deprivation being the significant contributor to the CNS findings noted in lactating rats exposed to HFO-1234ze. The dose associated with these effects (23,000 mg/kg/ day) is approximately 6000 times higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOEL (5763 mg/kg/day) and associated with a margin of approximately 1500 times (see section on Exposure and Margins of Safety).…”

Atmospheric fates and global warming potential of HFO-1234ze(E) and its degradation product trifluoroacetaldehyde (CF 3 CHO)

“…8 HCFC-141b was developed as an interim compound during the phase down of CFCs, and its production has been gradually phased out since 2003. 38 As the emissions inventory developed by Wang et al is not publicly available, we reproduced a variant for this work. Gridded emissions of HFO-1234ze(E) over China were generated as input for the HEMCO emissions component in GEOS-Chem.…”

The Nonclinical Assessment of Trans-1,3,3,3-tetrafluoropropene (HFO-1234ze (E)), a Near Zero Global Warming Potential Propellant for Use in Metered Dose Inhalation Products

“…24 Myocardial findings similar to those observed with HFO-1234ze have been reported in Sprague Dawley rats exposed to other HFCs such as HFC-245fa and HCFO-1233zd. 25 However, there were no HFO-1234ze related findings in the heart of dogs in the 39-week study or in the 13-week study in CD1 mice (for which this is also a common background finding) at any dose tested; it is important to note that the highest dose in the 13-week mouse study was 2.4-fold higher than in the 26-week rat study (29,000 mg/kg/day vs 12,000 mg/kg/day). While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf.…”

“…While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf. 25 The lack of cardiac findings in mice, dogs, and minipigs strongly suggests that the rat may be uniquely sensitive to the development of structural cardiac lesions such as RPCM following exposure to very high HFC doses; the effect dose in the 6 month rat study (12,000 mg/kg/day) is approximately more than 3000-fold higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOAEL (4280 mg/kg/day) and associated with a margin of approximately 1000 times (see section on Exposure and Margins of Safety).…”

“…These findings are consistent with the unexpected mortality of some lactating F0 and F1 rats in inhalation 2-generation rat studies with HFC-245fa 26 and HCFO-1233zd. 25 The underlying mechanism to explain the particular sensitivity of lactating rats to HFC exposure is not fully understood. Lactating females exposed to HFO-1234ze or HFC-245fa showed histopathology findings in the CNS characterized by neuronal necrosis, swelling of astrocytes, vacuolation of the neuropil, hemorrhage, and gliosis.…”

“…The nature of these histopathology findings are consistent with those observed following dosing with chemicals associated with so called acute "energy deprivation" syndromes, 27 or impaired energy metabolism. 25,28 Energy deprivation was cited as the likely cause of the CNS lesions in lactating rats exposed to HFC-245fa 26 and would support energy deprivation being the significant contributor to the CNS findings noted in lactating rats exposed to HFO-1234ze. The dose associated with these effects (23,000 mg/kg/ day) is approximately 6000 times higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOEL (5763 mg/kg/day) and associated with a margin of approximately 1500 times (see section on Exposure and Margins of Safety).…”

Atmospheric fates and global warming potential of HFO-1234ze(E) and its degradation product trifluoroacetaldehyde (CF 3 CHO)

“…8 HCFC-141b was developed as an interim compound during the phase down of CFCs, and its production has been gradually phased out since 2003. 38 As the emissions inventory developed by Wang et al is not publicly available, we reproduced a variant for this work. Gridded emissions of HFO-1234ze(E) over China were generated as input for the HEMCO emissions component in GEOS-Chem.…”

The Nonclinical Assessment of Trans-1,3,3,3-tetrafluoropropene (HFO-1234ze (E)), a Near Zero Global Warming Potential Propellant for Use in Metered Dose Inhalation Products

“…24 Myocardial findings similar to those observed with HFO-1234ze have been reported in Sprague Dawley rats exposed to other HFCs such as HFC-245fa and HCFO-1233zd. 25 However, there were no HFO-1234ze related findings in the heart of dogs in the 39-week study or in the 13-week study in CD1 mice (for which this is also a common background finding) at any dose tested; it is important to note that the highest dose in the 13-week mouse study was 2.4-fold higher than in the 26-week rat study (29,000 mg/kg/day vs 12,000 mg/kg/day). While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf.…”

“…While large animals were not routinely used in the toxicological assessment of HFCs, no cardiac findings were present in minipigs exposed to HFO-1234yf. 25 The lack of cardiac findings in mice, dogs, and minipigs strongly suggests that the rat may be uniquely sensitive to the development of structural cardiac lesions such as RPCM following exposure to very high HFC doses; the effect dose in the 6 month rat study (12,000 mg/kg/day) is approximately more than 3000-fold higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOAEL (4280 mg/kg/day) and associated with a margin of approximately 1000 times (see section on Exposure and Margins of Safety).…”

“…These findings are consistent with the unexpected mortality of some lactating F0 and F1 rats in inhalation 2-generation rat studies with HFC-245fa 26 and HCFO-1233zd. 25 The underlying mechanism to explain the particular sensitivity of lactating rats to HFC exposure is not fully understood. Lactating females exposed to HFO-1234ze or HFC-245fa showed histopathology findings in the CNS characterized by neuronal necrosis, swelling of astrocytes, vacuolation of the neuropil, hemorrhage, and gliosis.…”

“…The nature of these histopathology findings are consistent with those observed following dosing with chemicals associated with so called acute "energy deprivation" syndromes, 27 or impaired energy metabolism. 25,28 Energy deprivation was cited as the likely cause of the CNS lesions in lactating rats exposed to HFC-245fa 26 and would support energy deprivation being the significant contributor to the CNS findings noted in lactating rats exposed to HFO-1234ze. The dose associated with these effects (23,000 mg/kg/ day) is approximately 6000 times higher than that expected in humans with typical use of an MDI (2 × 2 inhalations per day); the lower dose tested was the NOEL (5763 mg/kg/day) and associated with a margin of approximately 1500 times (see section on Exposure and Margins of Safety).…”

Atmospheric fates and global warming potential of HFO-1234ze(E) and its degradation product trifluoroacetaldehyde (CF 3 CHO)

“…8 HCFC-141b was developed as an interim compound during the phase down of CFCs, and its production has been gradually phased out since 2003. 38 As the emissions inventory developed by Wang et al is not publicly available, we reproduced a variant for this work. Gridded emissions of HFO-1234ze(E) over China were generated as input for the HEMCO emissions component in GEOS-Chem.…”