Hazard identification and consumer safety characterization for trans-1-chloro-3,3,3-trifluoropropene (trans-1233zd).

Trans-1233zd was developed as a refrigerant and propellant in consumer products; its toxicity has been studied extensively. The scope of this assessment is to apply the confirmed NOAEC to conduct Benchmark Dose Modeling (BMD) and determine the Point of Departure (POD). In a previously published 13-week inhalation study, a NOAEC was identified at 4000 ppm. Due to uncertainty concerning the cardiac lesion, an external pathology peer review of heart tissues was undertaken using published best practices and consistent nomenclature and diagnostic criteria. The cardiac lesion observed at 4000 ppm was considered to be spontaneous based on lesion location and microscopic features. BMD was applied to derive the BMDL05 and BMDL10; the more conservative BMDL05 was used as the POD for risk assessment to calculate the Reference Exposure Levels (RELs). The 2-Box Air Dispersion Model was used to calculate the exposure to consumer products. Both the acute and chronic exposure concentrations calculated were compared to the acute and chronic RELs. The acute and chronic exposure to trans-1233zd in the assessed consumer products are below the RELs and deemed safe for their intended uses.

The development of environmentally acceptable fluorocarbons.

Chlorofluorocarbons (CFCs) were introduced in the 1930s as the safe replacements for the toxic and flammable refrigerants being used at that time. Subsequently, hydrochlorofluorocarbons (HCFCs) were also developed. In addition to refrigerant applications, they were used as foam blowing agents, as solvents and as propellants for many aerosols. In the 1970s and 1980s, concern developed about their environmental impact, specifically on stratospheric ozone depletion. Industry began to consider acceptable replacements. In 1987, many of the governments of the world came together and drafted the Montreal Protocol, calling upon Industry to initially phase out production of the CFCs and later HCFCs. Within 4 months of the signing of the Montreal Protocol, the 15 global major producers joined together to form the Alternative Fluorocarbons Environmental Acceptability Study (AFEAS), which sponsored research into environmental effects and the Program for Alternative Fluorocarbons toxicity Testing, PAFT), which examined the toxicology of potential replacements for the CFCs and HCFCs. Nine replacements were identified by companies and, through this international cooperation; toxicology programs were designed, conducted, and evaluated without duplication of effort and testing; consequently these new products were introduced within less than 10 years. Indeed the Montreal Protocol has been recognized as the most appropriate international treaty to phase-down HFCs. In 2016 the Kigali Amendment to the Montreal Protocol set out a phase-down schedule for the consumption and production of HFCs. In order to reduce the consumption and emissions of high GWP HFCs. Recently lower GWP HFCs and very low GWP HFOs (hydrofluoroolefins and HCFOs (hydrochlorofluoroolefins) have been introduced into a range of applications. Summaries of the toxicology profiles of some of the original CFCs and HCFCs, the replacements and the new post-PAFT replacements are described. The chemicals in this review include CFC-11, CFC-12, CFC-113, CFC-114, HCFC 22, HCFC-123, HCFC-124, HCFC-141b, HCFC-142b, HCF-32, HFC-125, HFC-134a, HFC-143a, HFC-152a, HFC-245ea, HFC-245fa, HFO-1234yf, HFO-1234ze, and HCFO-1233zd.

An approach for the development of emergency response levels for halogenated hydrocarbons.

Emergency exposure guidance levels have been developed for many halogenated hydrocarbons. These can be employed in the event of accidental releases or terrorist actions. However, for a chemical release involving a substance without existing guidance levels, there is a need to be able to develop one rapidly. Two data sources are available, the Acute Exposure Guideline Levels (AEGL) and Emergency Response Guideline Levels (ERPG). The subset of halogenated hydrocarbons and related substances included in these data sources represent 30 chemicals and 41 risk assessments. The ratios for serious toxicity/annoyance level and for potential lethality/serious toxicity were calculated. On reviewing the results, the geometric means provided the best basis for extrapolation. When the geometric means of the ratios of ERPG-3/ERPG-2 and AEGL-3/AEGL-2 were calculated their combined mean was 4.40. The geometric standard deviation for the combined data set was 2.00 suggesting the data were homogeneous. Likewise, calculation of the geometric means for ERPG-2/1 and AEGL-2/1 the combined ratio was 3.93. The geometric standard deviation for the combined set was 1.46, again suggesting homogeneity of the data. The review described in this paper confirmed that the time default "n" values of 3 and 1 (ten Berge et al., 1986) are appropriate for extrapolation to shorter and longer exposure times, respectively.

The acute, genetic, developmental and inhalation toxicology of trans-1-chloro,3,3,3-trifluoropropene (HCFO-1233zd(E)).

Trans-1-chloro,3,3,3-trifluoropropene (HCFO-1233zd(E)) is being developed as a foam blowing agent, refrigerant and solvent because it has a very low global warming potential (<10), as contrasted to the hydrofluorocarbons (>500). The toxicology profile is described. The acute 4-hour 50% lethal concentration value in rats receiving HCFO-1233zd(E) was 120 000 ppm. The no observed effect level (NOEL) in cardiac sensitization studies in dogs was 25 000 ppm. In a 2-week range-finding study, rats were exposed to HCFO-1233zd(E) at levels of 0, 2000, 7500 and 20 000 ppm 6 hours/day for 5 days/week. Histopathological changes in the heart described as multifocal mononuclear infiltrates were observed in males (mid- and high-exposure group) and females (high-exposure group), suggesting this organ was the target for HCFO-1233zd(E) toxicity. In a 4-week study, rats were exposed to 0, 2000, 4500, 7500 and 10 000 ppm. The only finding was an increase in potassium (mid- and high-exposure males). No increase was observed after a 2-week recovery period, nor in a subsequent 13-week toxicity study. In a 13-week study, rats were exposed to 4000, 10 000 and 15 000 ppm 6 hours/day for 5 days/week. Findings consisted of multifocal mononuclear cell infiltrates in the heart with a NOEL/lowest observed adverse effect level of 4000 ppm. No genetic toxicity was observed in a battery of genetic toxicity studies. In a rat prenatal developmental toxicity study, dilated bladders were observed in the high-exposure group fetuses (15 000 ppm), a finding of unclear significance. HCFO-1233zd(E) was not a developmental toxin in rabbits, even at exposure levels up to 15 000 ppm.

The acute, developmental, genetic and inhalation toxicology of 2,3,3,3-tetrafluoropropene (HFO-1234yf).

2,3,3,3-Tetrafluoropropene (HFO-1234yf) is being developed as a refrigerant because it has a very low global warming potential (less than 10), as contrasted to the hydrofluorocarbons, which is intended to replace with values of over 500. Several toxicology studies were conducted to develop a toxicology profile for this material. There was no lethality in mice and rats receiving single 4-hour exposures up to 101,850 or 405,800 ppm, respectively. Additionally, there was no mortality or clinical signs of toxicity when rabbits were exposed to 100,000 ppm for 1 hour. Exposures up to 120,000 ppm did not induce cardiac sensitization to adrenalin in dogs. Rats were exposed to HFO-1234yf at levels of 5000, 20,000 and 50,000 ppm 6 hours/day 5 days/week for 2 weeks and at levels of 5000, 15,000 and 50,000 ppm for 4 weeks and for 90 days. No treatment-related adverse effects were noted in these studies. HFO-1234yf was not genotoxic in a mouse and a rat micronucleus assay, and unscheduled DNA synthesis assay and was not clastogenic in human lymphocytes. HFO-1234yf was mutagenic to Salmonella typhimurium TA 100 and Escherichia coli (WP2 uvrA) at concentrations of 20% and higher in the presence of metabolic activation only. There were no biologically significant effects in a rat developmental toxicity study with exposures up to 50,000 ppm.

Biotransformation of trans-1-chloro-3,3,3-trifluoropropene (trans-HCFO-1233zd).

trans-1-Chloro-3,3,3-trifluoropropene (trans-HCFO-1233zd) is a novel foam blowing and precision cleaning agent with a very low impact for global warming and ozone depletion. trans-HCFO-1233zd also has a low potential for toxicity in rodents and is negative in genotoxicity testing. The biotransformation of trans-HCFO-1233zd and kinetics of metabolite excretion with urine were assessed in vitro and in animals after inhalation exposures. For in vitro characterization, liver microsomes from rats, rabbits and humans were incubated with trans-HCFO-1233zd. Male Sprague Dawley rats and female New Zealand White rabbits were exposed to 2,000, 5,000 and 10,000ppm for 6h and urine was collected for 48h after the end of the exposure. Study specimens were analyzed for metabolites using (19)F NMR, LC-MS/MS and GC/MS. S-(3,3,3-trifluoro-trans-propenyl)-glutathione was identified as predominant metabolite of trans-HCFO-1233zd in all microsomal incubation experiments in the presence of glutathione. Products of the oxidative biotransformation of trans-HCFO-1233zd were only minor metabolites when glutathione was present. In rats, both 3,3,3-trifluorolactic acid and N-acetyl-(3,3,3-trifluoro-trans-propenyl)-l-cysteine were observed as major urinary metabolites. 3,3,3-Trifluorolactic acid was not detected in the urine of rabbits. Quantitation showed rapid excretion of both metabolites in both species (t1/2<6h) and the extent of biotransformation of trans-HCFO-1233zd was determined as approximately 0.01% of received dose in rabbits and approximately 0.002% in rats. trans-HCFO-1233zd undergoes both oxidative biotransformation and glutathione conjugation at very low rates. The low extent of biotransformation and the rapid excretion of metabolites formed are consistent with the very low potential for toxicity of trans-HCFO-1233zd in mammals.

The acute, genetic, developmental and inhalation toxicology of trans-1,3,3,3-tetrafluoropropene (HFO-1234ze).

HFO-1234ze is being developed as a refrigerant, propellant, and foam-blowing agent because it has a very low global warming potential (less than 10), as contrasted to the hydrofluorocarbons with values of over 500. Several toxicology studies were conducted to develop a toxicology profile for this material. There was no lethality in mice and rats receiving single 4-hour exposures up to 103,300 or 207,000 ppm, respectively. Exposures up to 120,000 ppm did not induce cardiac sensitization to adrenalin. Rats were exposed to HFO-1234ze at levels of 5,000, 20,000, and 50,000 ppm 6 hours/day 5 days/week for 2 weeks. Predominate findings of increased liver and kidney weights and histopathological changes in the liver and heart suggested that these organs were the targets for HFO-1234ze toxicity. In a 4-week study at 1000, 5000, 10,000, and 15,000 ppm, the only organ showing treatment-related effects was the heart. In a 90-day study with exposures of 1500, 5000, and 15,000 ppm 6 hours/day 5 days/week, again, the heart was the only target organ. The findings consisted of focal and multifocal mononuclear cell infiltrates in the heart. There was no evidence of fibrosis, and, when compared to the 2- and 4-week studies, there did not appear to be an increase in severity with length of exposure. HFO-1234ze was inactive in a mouse and rat micronucleus assay, an Ames assay, and an unscheduled DNA synthesis assay and was not clastogenic in human lymphocytes. It was also not a developmental toxin in either the rat or rabbit, even at exposure levels up to15,000 ppm.

Biotransformation of 2,3,3,3-tetrafluoropropene (HFO-1234yf) in male, pregnant and non-pregnant female rabbits after single high dose inhalation exposure.

2,3,3,3-Tetrafluoropropene (HFO-1234yf) is a novel refrigerant intended for use in mobile air conditioning. It showed a low potential for toxicity in rodents studies with most NOAELs well above 10,000 ppm in guideline compliant toxicity studies. However, a developmental toxicity study in rabbits showed mortality at exposure levels of 5,500 ppm and above. No lethality was observed at exposure levels of 2,500 and 4,000 ppm. Nevertheless, increased subacute inflammatory heart lesions were observed in rabbits at all exposure levels. Since the lethality in pregnant animals may be due to altered biotransformation of HFO-1234yf and to evaluate the potential risk to pregnant women facing a car crash, this study compared the acute toxicity and biotransformation of HFO-1234yf in male, female and pregnant female rabbits. Animals were exposed to 50,000 ppm and 100,000 ppm for 1h. For metabolite identification by (19)F NMR and LC/MS-MS, urine was collected for 48 h after inhalation exposure. In all samples, the predominant metabolites were S-(3,3,3-trifluoro-2-hydroxypropanyl)-mercaptolactic acid and N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine. Since no major differences in urinary metabolite pattern were observed between the groups, only N-acetyl-S-(3,3,3-trifluoro-2-hydroxypropanyl)-L-cysteine excretion was quantified. No significant differences in recovery between non-pregnant (43.10 ± 22.35 µmol) and pregnant female (50.47 ± 19.72 µmol) rabbits were observed, male rabbits exposed to 100,000 ppm for one hour excreted 86.40 ± 38.87 µmol. Lethality and clinical signs of toxicity were not observed in any group. The results suggest that the lethality of HFO-1234yf in pregnant rabbits unlikely is due to changes in biotransformation patterns or capacity in pregnant rabbits.

Comparative reprotoxicity of three oximes.

One-generation reproductive toxicity studies have been conducted on the following three oximes: acetaldehyde oxime (AAO), aldecarb oxime (ADO), and methyl isobutyl ketoxime (MIBKO). The studies followed the OECD 415 guideline (One-Generation Reproduction Toxicity Study), with a few modifications. Rats were exposed to the test material for 10 weeks prior to mating and 2 weeks of mating. Males were killed following mating, and females were continuously exposed through gestation and lactation. For MIBKO, the F1 generation was exposed from weaning until approximately 7 weeks of age to include when the vaginal opening occurred in females or when balanopreputial separation occurred in males. With the exception of an increased number of stillbirths in the ADO high-dose-group animals, no adverse effects were observed in any of the reproductive or litter parameters or in the F1 pups. Toxicity to the F0 animals included signs of hemolytic anemia, along with compensatory extramedullary hematopoiesis and hemosiderosis of the spleen. This occurred for all three test materials. For AAO, the no-observed-adverse-effect level (NOAEL) for the F0 generation was considered to be less than 5 mg/kg/day, based on decreased mean corpuscular hemoglobin concentration values and histological changes in the spleen. The NOAEL for the F1 generation and reproductive toxicity was considered to be 50 mg/kg/day, the highest dose tested. For ADO, the NOAEL for parental toxicity was considered to be less than 5 mg/kg/day, based on the histological changes observed in the livers of females in all groups. The NOAEL for reproductive toxicity and the F1 generation was considered to be 25 mg/kg/day, based on the higher number of stillborn pups in the high-dose group. For MIBKO, the NOAEL for parental toxicity was considered to be 30 mg/kg/day, based on the histological effects on the spleen. The NOAEL for the F1 generation and reproductive toxicity was 100 mg/kg/day, the highest dose tested.

Biotransformation of trans-1,1,1,3-tetrafluoropropene (HFO-1234ze).

trans-1,1,1,3-Tetrafluoropropene (HFO-1234ze) is a non-ozone-depleting fluorocarbon replacement with a low global warming potential and is developed as foam blowing agent. The biotransformation of HFO-1234ze was investigated after inhalation exposure. Male Sprague-Dawley rats were exposed to air containing 2000; 10,000; or 50,000 ppm (n=5/concentration) HFO-1234ze. Male B6C3F1 mice were only exposed to 50,000 ppm HFO-1234ze. All inhalation exposures were conducted for 6 h in a dynamic exposure chamber. After the end of the exposures, animals were individually housed in metabolic cages and urines were collected at 6 or 12 h intervals for 48 h. For metabolite identification, urine samples were analyzed by (1)H-coupled and (1)H-decoupled (19)F-NMR and by LC/MS-MS or GC/MS. Metabolites were identified by (19)F-NMR chemical shifts, signal multiplicity, (1)H-(19)F coupling constants and by comparison with synthetic reference compounds. In urine samples of rats exposed to 50,000 ppm HFO-1234ze, the predominant metabolite was S-(3,3,3-trifluoro-trans-propenyl)-mercaptolactic acid and accounted for 66% of all integrated (19)F-NMR signals in urines. No (19)F-NMR signals were found in spectra of rat urine samples collected after inhalation exposure to 2000 or 10,000 ppm HFO-1234ze likely due to insufficient sensitivity. S-(3,3,3-Trifluoro-trans-propenyl)-l-cysteine, N-acetyl-S-(3,3,3-trifluoro-trans-propenyl)-l-cysteine and 3,3,3-trifluoropropionic acid were also present as metabolites in urine samples of rats and mice. A presumed amino acid conjugate of 3,3,3-trifluoropropionic acid was the major metabolite of HFO-1234ze in urine samples of mice exposed to 50,000 ppm and related to 18% of total integrated (19)F-NMR signals. Quantification of three metabolites in urines of rats and mice was performed, using LC/MS-MS and GC/MS. The quantified amounts of the metabolites excreted with urine in both mice and rats, suggest only a low extent (<1% of dose received) of biotransformation of HFO-1234ze and 95% of all metabolites were excreted within 18 h after the end of the exposures (t(1/2) app. 6 h). The obtained results suggest that HFO-1234ze is likely subjected to an addition-elimination reaction with glutathione and to a CYP 450 mediated epoxidation at low rates.

Establishing a point of departure for risk assessment using acute inhalation toxicology data.

A simple method is presented for estimating a non-lethal level for inhalation toxicity studies. By reviewing 209 LC(50) studies representing 96 chemicals that also reported a non-lethal level, it has been shown that taking 1/3 of the LC(50) is a conservative estimate for a non-lethal exposure level. This approach was also compared to studies with LC(01) and BMCL(05) calculations. In the 38 studies that reported either of these values, again taking 1/3 of the LC(50) provided a more conservation estimate for the non-lethal threshold. The studies included time intervals from 5min out to 8h and utilized multiple species such as the rat, mouse, hamster, guinea pig and dog. In all but 13 cases, taking 1/3 of the LC(50) provided a more conservative estimate for a non-lethal exposure level compared to the experimentally observed value. In all but one of the 13 cases, the higher values were consequences of the selection of the exposure levels.

Biotransformation of 2,3,3,3-tetrafluoropropene (HFO-1234yf).

2,3,3,3-Tetrafluoropropene (HFO-1234yf) is a non-ozone-depleting fluorocarbon replacement with a low global warming potential which has been developed as refrigerant. The biotransformation of HFO-1234yf was investigated after inhalation exposure. Male Sprague-Dawley rats were exposed to air containing 2000, 10,000, or 50,000 ppm HFO-1234yf for 6 h and male B6C3F1 mice were exposed to 50,000 ppm HFO-1234yf for 3.5 h in a dynamic exposure chamber (n=5/concentration). After the end of the exposure, animals were individually housed in metabolic cages and urines were collected at 6 or 12-hour intervals for 48 h. For metabolite identification, urine samples were analyzed by (1)H-coupled and decoupled (19)F-NMR and by LC/MS-MS or GC/MS. Metabolites were identified by (19)F-NMR chemical shifts, signal multiplicity, (1)H-(19)F coupling constants and by comparison with synthetic reference compounds. In all urine samples, the predominant metabolites were two diastereomers of N-acetyl-S-(3,3,3-trifluoro-2-hydroxy-propyl)-l-cysteine. In (19)F-NMR, the signal intensity of these metabolites represented more than 85% (50,000 ppm) of total (19)F related signals in the urine samples. Trifluoroacetic acid, 3,3,3-trifluorolactic acid, 3,3,3-trifluoro-1-hydroxyacetone, 3,3,3-trifluoroacetone and 3,3,3-trifluoro-1,2-dihydroxypropane were present as minor metabolites. Quantification of N-acetyl-S-(3,3,3-trifluoro-2-hydroxy-propyl)-l-cysteine by LC/MS-MS showed that most of this metabolite (90%) was excreted within 18 h after the end of exposure (t(1/2) app. 6 h). In rats, the recovery of N-acetyl-S-(3,3,3-trifluoro-2-hydroxy-propyl)-l-cysteine excreted within 48 h in urine was determined as 0.30+/-0.03, 0.63+/-0.16, and 2.43+/-0.86 micromol at 2000, 10,000 and 50,000 ppm, respectively suggesting only a low extent (<<1% of dose received) of biotransformation of HFO-1234yf. In mice, the recovery of this metabolite was 1.774+/-0.4 mumol. Metabolites identified after in vitro incubations of HFO-1234yf in liver microsomes from rat, rabbit, and human support the metabolic pathways of HFO-1234yf revealed in vivo. The obtained results suggest that HFO-1234yf is subjected to a typical biotransformation reaction for haloolefins, likely by a cytochrome P450 2E1-catalyzed formation of 2,3,3,3-tetrafluoroepoxypropane at low rates, followed by glutathione conjugation or hydrolytic ring opening.

Respiratory irritation associated with inhalation of boron trifluoride and fluorosulfonic acid.

The objectives of this study were to examine the respiratory irritancy of boron trifluoride (BF(3)) and fluorosulfonic acid (FSA) following acute inhalation exposure. Testing was conducted using groups of 10 male and 10 female rats (BF(3)) or groups of 6 male rats (FSA). Rats were exposed for a single 4-h period (BF(3)) or a single 1-h period (FSA) and necropsied 1 or 14 days after exposure (BF(3)) or 14 days after exposure (FSA). Measurements consisted of clinical signs, body weight, kidney and lung weight, histopathology (BF(3)), and breathing parameters (FSA) and were used to evaluate the possible irritating effects of these compounds. The results indicated treatment-related findings in the larynx and trachea in the rats exposed to 74.4 mg/m(3) BF(3), consisting of ventral cartilage necrosis, hemorrhage, and an increase in ventral epithelial hyperplasia and ventral inflammatory cell inflammation 24 h postexposure. In the animals sacrificed 14 days postexposure, the only notable observation was ventral cartilage necrosis, present in 2 animals. The next lower level tested, 24.6 mg/m(3) BF, was considered a no-observed-adverse-effects level (NOAEL). A concentration of 4125 mg/m(3) FSA resulted in a clearly decreased breathing rate during and shortly after exposure with 67% (4/6) mortality on days 5-9 after exposure. A concentration of 845 mg/m(3) FSA resulted in only minor signs of irritation, consisting of slight changes in breathing pattern shorlty after exposure. The results of the present 4-h inhalation study with BF(3) indicated that respiratory irritation was present at a level of 74.4 mg/m(3) whereas 24.6 mg/m(3) was a NOAEL. A single 1-h exposure to 845 mg/m(3) FSA resulted in only minor signs of respiratory irritation, indicating that on a mass basis FSA is no more toxic or irritating than hydrogen fluoride (HF) or sulfuric acid.

Oxime silanes: structure/toxicity relationships.

Acute and repeated oral and dermal rat toxicology studies of standard designs were conducted on four methyl ethyl ketoxime (MEKO) silanes and four methyl isobutyl ketoxime (MIBKO) silanes. Each compound contained either MEKO or MIBKO groups (but not both) and either a single methyl, vinyl, or phenyl group (trifunctional oxime silane), two methyl groups or a methyl and vinyl group (difunctional oxime silane), or no nonoxime group (tetrafunctional oxime silane) attached to the central silicon atom. All compounds caused transient narcosis and anemia, with oral exposure associated with the hydrolyzed oxime groups. Difunctional oxime silanes, containing both a methyl and a vinyl group, caused degeneration of the seminiferous tubules of the testes following oral administration. Serial testicular histopathology indicated the effect originated at the level of the spermatocyte, resulting in a wave of cellular depletion of later maturation stages of spermatogenesis. Spermatogenesis gradually recovered but function was not evaluated. Tetrafunctional oxime silanes, trifunctional oxime silanes, including those containing a single methyl or vinyl group, or difunctional oxime silane containing two methyl groups did not affect the testes, indicating that both a methyl and vinyl group needs to be present on the oxime silane molecule for testicular toxicity. The testicular toxicity appears to be associated with the methyl/vinyl silane portion and not the oxime portion of the oxime silane molecule. With the exception of the methyl/vinyl difunctional oxime silanes, the silane portion of oxime silanes does not appear to contribute any significant toxicity to these compounds.

Cardiac sensitization: methodology and interpretation in risk assessment.

An increased sensitivity of the heart to endogenous epinephrine (adrenaline), a phenomenon referred to as cardiac sensitization, has long been recognized as a risk during exposure to hydrocarbons, principally halogenated hydrocarbons. Cardiac sensitization, which can result in serious arrhythmia and death, requires a certain critical blood level of both the sensitizing agent and epinephrine. The original research and methods utilized an exogenous epinephrine challenge during inhalation exposure to a chemical to assess cardiac sensitization potential in Beagle dogs. These screening tests were developed about 30 years ago, although in the last 15 years some modifications of these methods have occurred in response to testing chlorofluorocarbon (CFC) replacements. Results from these experimental cardiac sensitization studies have been used for semi-quantitative risk evaluation for occupational exposures but now are being used more quantitatively for regulatory purposes. The risks associated with cardiac sensitization from CFC replacements are unknown but expected to be low based on cardiac sensitization studies in the 1970s where dogs were made to generate their own adrenaline. With the advent of physiologically based pharmacokinetic (PBPK) modeling, greater emphasis is being placed on quantitative risk assessment for cardiac sensitization. In this investigation, we have examined the various methodologies used for detection of cardiac sensitization and discussed their limitations and advantages. In addition, we examined the potential concerns involved in using experimental cardiac sensitization data and PBPK modeling to predict exposure scenarios.

Hepatotoxicity associated with overexposure to 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123).

1,1-Dichloro-2,2,2-trifluoroethane (HCFC-123) was evaluated as a substitute for trichlorofluoromethane (CFC-11), and it appeared that a permissible exposure limit of 50 ppm was justified. When HCFC-123 was introduced as a precision cleaning agent in a controlled operation, marked elevations in serum alanine transaminase and serum aspartase transaminase were noted in exposed workers. Sampling taken during start-up documented personal samples from 24-480 ppm (375 and 21 min, respectively) and area samples of 18-180 ppm (375 and 21 min, respectively). Personal and area samples collected after the liver abnormalities were identified ranged from 5-12 ppm. Exposure data were not available for the period when the abnormalities are suspected to have developed. Two models were developed to estimate exposure during the unmonitored period: (1) the entire plant as a homogenous box and (2) evaporation into smaller work zones. Modeling using the entire building estimated 8-hour time-weighted average (TWA) exposures of 10-35 ppm. Modeled estimates of work area and air exchange rates indicated that degreaser exposed workers could have experienced peak levels of 280-2,100 ppm (8-hour TWAs 252-1,630 ppm). Modeling of the work environment, estimated to be one-third of the volume of the entire open building, indicated peak exposures of 28-210 ppm (8-hour TWAs 25-163 ppm). These ranges estimate the minimum and maximum exposure levels. The best estimates, using 12 air changes per day, suggest peak levels around the degreaser of 635-2,100 ppm (8-hour TWA 499-1,630 ppm) and 63-207 ppm (8-hour TWAs 50-163 ppm) in the work area. These are the first estimates of exposure level associated with these hepatotoxic effects; all are significantly higher than personal and area samples collected for HCFC-123 after the liver abnormalities were identified.

The development of acute exposure guideline levels for hazardous substances.

The National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL) was created to develop guideline levels for short-term exposures to airborne concentrations for approximately 400-500 high priority, acutely hazardous substances. The program should be completed within the next 10 years. These Acute Exposure Guideline Levels (AEGLs) are being applied to a wide range of planning, response, and prevention applications both within the United States and abroad. The NAC/AEGL Committee seeks to develop the most scientifically credible, acute (short-term) exposure guideline levels possible within the constraints of data availability, resources and time. The program begins with comprehensive data gathering, data evaluation and data summarization. The resulting Technical Support Documents (TSD) are first reviewed by a small review committee; (chemical manager, two chemical reviewers and the author), then by the full AEGL committee. After that review, a summary is published in the Federal Register for Public comment. When these comments have been addressed, the TSDs are sent to the National Research Council's (NRC) Subcommittee on AEGLs for a peer review. Following acceptance by the NRC, they are published by the Academy. The NAC/AEGL Committee currently comprises representatives of federal, state, and local agencies and representatives from France, Germany, and the Netherlands, private industry, medicine, academia and other organizations in the private sector that will derive programmatic or operational benefits from the existence of the AEGL values. AEGL values are determined for three different health effect end-points. These values are intended for the general public where they are applicable to emergency (accidental) situations. Threshold exposure values are developed for five exposure periods (10 and 30 min, 1 h, 4 h, 8 h). Each threshold value is distinguished by varying degrees of severity of toxic effects, as initially conceived by the American Industrial Hygiene Association's Emergency Response Planning Committee, subsequently defined in the NAS' National Research Council publication of the Guideline for Developing Community Emergency Exposure Levels for Hazardous Substances and further categorized in the Standing Operating Procedures of the NAC/AEGL Committee. To date, the committee has reviewed almost 100 chemicals.

Biotransformation of 1,1,1,3,3-Pentafluoropropane (HFC-245fa).

1,1,1,3,3-Pentafluoropropane (HFC-245fa) is being developed as a CFC substitute. 1,1,1,3,3-Pentafluoropropane has a low potential for toxicity: the only remarkable toxic effect seen in rats after inhalation exposure to 1,1,1,3,3-pentafluoropropane in concentrations of up to 50,000 ppm for 90 days was an increased incidence of diffuse myocarditis. To elucidate the possible role of biotransformation in 1,1,1,3,3-pentafluoropropane-induced cardiotoxicity, the biotransformation of 1,1,1,3,3-pentafluoropropane was investigated in rats after inhalation exposure and in rat and human liver microsomes. Male and female rats were exposed by inhalation to 50 000, 10 000, and 2000 ppm 1,1,1,3,3-pentafluoropropane for 6 h, urine was collected for 72 h, and metabolites excreted were identified by 19F NMR spectroscopy and quantified by GC/MS. Trifluoroacetic acid and inorganic fluoride were identified as major urinary metabolites of 1,1,1,3,3-pentafluoropropane; 3,3,3-trifluoropropanoic acid and 1,1,1,3,3-pentafluoropropane-2-ol were minor metabolites. The extent of 1,1,1,3,3-pentafluoropropane biotransformation after inhalation was dependent on exposure concentrations. Neither 3,3,3-trifluoropropanoic acid nor 3,3,3-trifluoropyruvic acid were metabolized to trifluoroacetic acid in vitro or in rats. In rat and human liver microsomes, 1,1,1,3,3-pentafluoropropane was biotransformed by a cytochrome P450-dependent reaction to trifluoroacetic acid and 3,3,3-trifluoropropanoic acid. Rates of trifluoroacetic acid formation were 99.2 +/- 20.5 pmol (mg of protein)(-)(1) min(-)(1) and of 3,3,3-trifluoropropanoic acid formation were 17.5 +/- 4.0 pmol (mg of protein)(-)(1) min(-)(1) in liver microsomes from male rats. In human liver microsomes, rates of trifluoroacetic acid formation ranged from 0 to 11.6 pmol (mg of protein)(-)(1) min(-)(1), and rates of 3,3,3-trifluoropropanoic acid formation ranged from 0.7 to 7.6 pmol (mg of protein)(-)(1) min(-)(1). The results show that 1,1,1,3,3-pentafluoropropane is metabolized at low rates in vivo and in vitro. The toxic effects of 1,1,1,3,3-pentafluoropropane may be associated with the formation of the minor metabolite 3,3,3-trifluoropropanoic acid, which is highly toxic in rats.