Unexpected brain lesions in lactating Sprague-Dawley rats in a Two-generation Inhalation Reproductive Toxicity Study with pentafluoropropane (HFC-245fa).

The study presented was conducted following the reproductive study guideline OECD Guideline 416 Two-Generation Reproduction Toxicity Study. Sprague-Dawley rats were exposed to 2000, 10,000 and 50,000 ppm of HFC-245fa. There was an unexpected mortality of lactating dams in the medium and high dose group beginning at day 10 of lactation. Statistically significant histopathological alterations were observed in the cerebellum of a total of 9/30 females of the high dose group of the F0-generation and in 10/27 females of the high dose group of the F1-generation. In contrast there were no brain lesions found in males or non-pregnant females of all dose groups. Neuronal necrosis and degeneration in the cerebellar cortex were observed as the most severe finding. Furthermore vacuolation of the neuropil in different degrees was diagnosed in 7/30 females of the F0-generation and in 9/30 females of the F1-generation. Acute hemorrhages - in particular perivascular - occurred in 5/30 females of the F0- and in 5/30 females of the F1-generation indicating a disturbed vascular integrity. The main lesions found in the cerebrum were glial scars in the corpus callosum and restricted to 2/30 females of the F0-generation of the high dose group. The increased incidence of myocardial fibrosis and mononuclear cell infiltration in males - indicating myocarditis - was only seen in the F0-generation of the high dose group. Females of the F1-generation of the high dose group showed an increased incidence of minimal myocardial fibrosis. In summary, histopathology revealed that the brain, particularly the cerebellum, and to a minor degree the heart turned out to be the toxicological target organs of the substance. Presumably substance-related energy deprivation may be responsible for the observed changes. One of the metabolites, 3,3,3-trifluoropropanoic acid has been shown to be capable of causing this effect.

Environmental service payments: evaluating biodiversity conservation trade-offs and cost-efficiency in the Osa Conservation Area, Costa Rica.

The cost-efficiency of payments for environmental services (PES) to private landowners in the Osa Conservation Area, Costa Rica, is evaluated in terms of the trade-off between biodiversity representation and opportunity costs of conservation to agricultural and forestry land-use. Using available GIS data and an 'off-the-shelf' software application called TARGET, we find that the PES allocation criteria applied by authorities in 2002-2003 were more than twice as cost-efficient as criteria applied during 1999-2001. Results show that a policy relevant assessment of the cost-effectiveness of PES relative to other conservation policies can be carried out at regional level using available studies and GIS data. However, there are a number of data and conceptual limitations to using heuristic optimisation algorithms in the analysis of the cost-efficiency of PES. Site specific data on probabilities of land-use change, and a detailed specification of opportunity costs of farm land, labour and capital are required to use algorithms such as TARGET for ranking individual sites based on cost-efficiency. Despite its conceptual soundness for regional conservation analysis, biodiversity complementarity presents a practical challenge as a criterion for PES eligibility at farm level because it varies depending on the set of areas under PES contracts at any one time.

Human safety and pharmacokinetics of the CFC alternative propellants HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3, 3-heptafluoropropane) following whole-body exposure.

HFC 134a (1,1,1,2-tetrafluoroethane) and HFC 227 (1,1,1,2,3,3, 3-heptafluoropropane) are used to replace chlorofluorocarbons (CFCs) in refrigerant and aerosol applications, including medical use in metered-dose inhalers. Production and consumption of CFCs are being phased out under the Montreal Protocol on Substances that Deplete the Ozone Layer. The safety and pharmacokinetics of HFC 134a and HFC 227 were assessed in two separate double-blind studies. Each HFC (hydrofluorocarbon) was administered via whole-body exposure as a vapor to eight (four male and four female) healthy volunteers. Volunteers were exposed, once weekly for 1 h, first to air and then to ascending concentrations of HFC (1000, 2000, 4000, and 8000 parts per million (ppm)), interspersed with a second air exposure and two CFC 12 (dichlorodifluoromethane) exposures (1000 and 4000 ppm). Comparison of either HFC 134a or HFC 227 to CFC 12 or air gave no clinically significant results for any of the measured laboratory parameters. There were no notable adverse events, there was no evidence of effects on the central nervous system, and there were no symptoms of upper respiratory tract irritation. HFC 134a, HFC 227, and CFC 12 blood concentrations increased rapidly and in an exposure-concentration-dependent manner, although not strictly proportionally, and approached steady state. Maximum blood concentrations (C(max)) tended to be higher in males than females; in the HFC 227 study, these were statistically significantly (P < 0. 05) higher in males for each HFC 227 and CFC 12 exposure level. In the HFC 134a study, the gender difference in C(max) was only statistically significant (P < 0.05) for CFC 12 at 4000 ppm and HFC 134a at 8000 ppm. Following the end of exposure, blood concentrations declined rapidly, predominantly biphasically and independent of exposure concentration. For the HFC 134a study, the t(1/2)alpha (alpha elimination half-life) was short for both CFC 12 and HFC 134a (<11 min). The t(1/2)beta (beta elimination half-life) across all exposure concentrations was a mean of 36 and 42 min for CFC 12 and HFC 134a, respectively. Mean residence time (MRT) was an overall mean of 42 and 44 min for CFC 12 and HFC 134a, respectively. In the HFC 227 study, t(1/2)alpha for both CFC 12 and HFC 227, at each exposure level, was short (<9 min) and tended to be lower in males than females. For CFC 12 mean t(1/2)beta ranged from 23 to 43 min and for HFC 227 the mean range was 19-92 min. The values tended to be lower for females than males for HFC 227. For both CFC 12 and HFC 227, MRT was statistically significantly lower (P < 0.05) in males than females and independent of exposure concentration. For CFC 12, MRT was a mean of 37 and 45 min for males and females, respectively, and for HFC 227 MRT was a mean of 36 and 42 min, respectively. Exposure of healthy volunteers to exposure levels up to 8000 ppm HFC 134a, 8000 ppm HFC 227, and 4000 ppm CFC 12 did not result in any adverse effects on pulse, blood pressure, electrocardiogram, or lung function.

Inhalation toxicity and genotoxicity of hydrochlorofluorocarbon (HCFC)-225ca and HCFC-225cb.

The acute, subchronic and genetic toxicity of the hydrochlorofluorocarbons HCFC-225ca and HCFC-225cb were evaluated to assist in establishing proper handling guides. In acute inhalation studies, rats were exposed for 4 h to various concentrations of each isomer. Based on the mortality incidence, the LC50 value for HCFC-225cb for males and females (combined) was 36800 ppm. For HCFC-225ca, the LC50 for males and females (combined) was 37300 ppm. Narcotic-like effects, e.g. prostration, incoordination and reduced motor activity, were observed during exposure to either isomer, but these signs were not evident 15 min after termination of exposure. Histopathological examination of the liver revealed an increase in mitotic figures with vacuolation of hepatocytes and fluid-filled, congested hepatic sinusoids. In cardiac sensitization studies, HCFC-225cb induced a cardiac sensitization response at 20000 ppm, with one fatal response, whereas a blend of the two isomers (45% HCFC-225ca/55% HCFC-225cb) produced a cardiac sensitization response at 15000 ppm. In 4-week subchronic inhalation studies, male and female rats were whole-body exposed to HCFC-225cb at concentrations of 0, 1000, 5000 or 15000 ppm for 6 h a day, 5 days per week. Similarly, male and female rats were whole-body exposed to HCFC-225ca concentrations of 0, 50, 500 or 5000 ppm for 6 h a day, 5 days per week. During exposure, narcotic-like and irritant effects were observed. A dose-related decrease in cholesterol and triglycerides was observed in the treated rats, with males being affected more than females. Increases in liver weight were observed in most male and female rats exposed to either isomer. The increase in liver weight was consistent in male rats with microscopic evidence of hepatocyte hypertrophy. Although liver weight was increased in female rats, no hepatocyte enlargement was observed in treated female rats. Increases in cytochrome P-450 and beta-oxidation activities were also observed in male and female rats exposed to either isomer. Neither of the HCFC-225 isomers was mutagenic in the Ames reverse mutation assay, or clastogenic in the chromosomal aberration assay with Chinese hamster lung cells. Also, neither isomer induced unscheduled DNA synthesis in liver cells. However, both isomers were clastogenic in the chromosomal aberration assay with human lymphocytes in the absence of S-9. No increases in aberrant cells were observed in activated cells exposed to either isomer.

The acute, genetic, developmental, and inhalation toxicology of 1,1,1,3,3-pentafluoropropane (HFC 245fa).

1,1,1,3,3-Pentafluoropropane (HFC 245fa) is a volatile, low boiling liquid. It was inactive in a reverse mutation (Ames) assay using five strains of Salmonella typhimurium and one strain of Escherichia coli. It was also inactive in an in vivo mouse micronucleus assay with exposures of 101,000 ppm. In a chromosome aberration study with human lymphocytes, some activity was seen when cell cultures were exposed to atmospheres of 30% v/v or higher for 24 h without metabolic activation. No activity was seen in assays using less than 30% v/v or exposure times of less than 24 h. No activity was seen in the presence of metabolic activation even with exposures of 70%. It was not toxic by the dermal route. There was no mortality or significant signs of toxicity when rats and mice were given 4- h exposures to levels of 203,000 ppm or 101,000 ppm of HFC 245fa, respectively. In a cardiac sensitization study with dogs involving intravenous administration of epinephrine, the no observed effect level (NOEL) was 34,000 ppm and the threshold for a response was 44,000 ppm. In a rat inhalation, developmental toxicity study, a slight reduction in pup weight was seen at 50,000 ppm, but not at 10,000 ppm. There were no developmental effects at any level. A series of three inhalation toxicity studies were conducted. All involved daily 6-h exposures up to 50,000 ppm. The first study involved 14 consecutive snout-only exposures. There were no treatment-related effects on body weight, survival, or histologic parameters. BUN, GPT, and GOT levels frequently were elevated compared to controls , whereas cholesterol levels tended to be lower. The second study involved 28 consecutive whole-body exposures. Again, there were no treatment related effects on body weight, survival, or histological parameters. Urine volume was increased. Increases were also seen in several red blood cell parameters. These may be related to partial dehydration. Increases were seen in BUN levels and alkaline phosphatase (AP), GPT, GOT and CPK activities, primarily in rats exposed at 10,000 and 50,000 ppm. Urinary fluoride levels were also elevated in an exposure- related pattern. In the third study, whole-body exposures were conducted 5 days per week for 13 weeks. There were no treatment-related effects on survival, clinical observations, body weight gain, or food consumption. Urine volumes were increased, urinary fluoride levels were elevated, and increases were seen in red blood cell counts, and related parameters and increases were seen in AP, GOT, GPT and CPK activities. These effects were seen in the 10,000 and 50,000 ppm exposure level groups. Histopathologic examination did not show any effects on the kidney, liver, or lungs. There was an increased incidence of myocarditis in all animals exposed at 50,000 ppm and the majority exposed at 10,000 ppm. It was described as mild. Based on these findings, 2000 ppm appears to be a no observed adverse effect level.

Chronic toxicity, oncogenicity, and mutagenicity studies with chlorotetrafluoroethane (HCFC-124).

The chronic toxicity, oncogenicity, and mutagenicity of chlorotetrafluoroethane (HCFC-124) were evaluated. In the chronic toxicity/oncogenicity study, male and female rats were exposed to 0, 2000, 10,000, or 50,000 ppm HCFC-124 for 6 hr/day, 5 days/week, for 2 years. Body weights were obtained weekly during the first three months of the study and every other week for the remainder of the study. Food consumption was determined weekly. Clinical signs of toxicity were monitored throughout the study. An ophthalmological examination was performed on all animals prior to study start, and all surviving rats were examined at approximately 3, 12, and 24 months after study start. Clinical pathology was evaluated at 3, 6, 12, 18, and 24 months. An interim termination was conducted at 12 months. All surviving rats were necropsied at 24 months. A complete set of tissues was collected for microscopic examination, and selected tissues were weighed. There were no compound-related, adverse effects on body weight, food consumption, survival, clinical signs of toxicity, ophthalmoscopically observable ocular lesions, serum hormone concentrations, or clinical pathology parameters at any exposure concentration in either male or female rats. Compared to controls, urine fluoride was increased in males and females at all exposure concentrations, and plasma fluoride was increased in females at all exposure concentrations. Excretion of fluoride represents conversion of the parent molecule, and as such is not considered to be an adverse effect. There were no toxicologically significant, compound-related organ weight changes or gross or microscopic findings in male or female rats at any of the exposure concentrations tested. HCFC-124 was not toxic or carcinogenic in rats of either sex after inhalation exposure at concentrations of up to 50,000 ppm in this two-year chronic toxicity/oncogenicity study. After exposure to HCFC-124 for six hours per day, five days per week, for 24 months, the no-observed-adverse-effect level for male and female rats was 50,000 ppm. HCFC-124 was not mutagenic in Salmonella typhimurium strains TA1535, TA97, TA98, and TA100 with and without activation when evaluated at concentrations up to 60% HCFC-124 for 48 hours. No evidence of clastogenic activity was observed in cultured human lymphocytes at atmospheric concentrations up to 100% HCFC-124 for 3 hours, with and without metabolic activation. In vivo, no micronuclei were induced in mouse bone marrow cells following exposure of mice to concentrations of 99,000 ppm HCFC-124 6 hours/day for 2 days.

Subchronic inhalation toxicity study of caprolactam (with a 4-week recovery) in the rat via whole-body exposures.

This study was designed to assess the potential subchronic inhalation toxicity of caprolactam when administered as a 3-micron aerosol from an aqueous solution to Sprague-Dawley CD rats (10/sex/group) via whole-body exposure. The study was enhanced with the inclusion of motor activity measurements and a functional observational battery to assess the neurotoxic potential of caprolactam. The rats were exposed at least 65 times over a 13-week period for 6 h per day, 5 days per week, to target concentrations (3 microns, mass median aerodynamic diameter) of 0, 25, 75, and 250 milligrams per cubic meter (mg/m3). An additional 10 animals/sex/group were similarly exposed and then held for a 4-week recovery period. Exposure levels were determined gravimetrically six times daily; one daily sample was analyzed by high-pressure liquid chromatography. No deaths were observed in the study during the exposure or recovery periods. Treatment-related responses such as labored breathing and nasal discharge were seen during many of the exposures. Similar responses as well as moist rales were seen during the nonexposure periods during the 13 weeks of exposure. However, these responses abated during the 4-week recovery period. There were no clearly treatment-related responses observed with ophthalmoscopic examinations, body weight measurements, food consumption measurements, neurobehavioral evaluations, clinical pathology evaluations, organ weight measurements, or macroscopic pathology examinations. Microscopic findings that were considered related to exposure to the test material were seen in the nasoturbinal tissues (hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the olfactory mucosa) of the two higher-exposure group animals and in the laryngeal tissues (squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromucous gland) of all three exposure group animals. These changes were considered to be adaptive responses to an irritant (caprolactam). The keratinization of the metaplastic epithelium in the larynx was considered to be an adverse effect. By the end of the 4-week recovery period, there was complete regression of the keratinization in the larynx, but recovery of the adaptive nasoturbinal effects had not completely resolved. In conclusion, the whole-body exposure of Sprague-Dawley rats to caprolactam as a respirable aerosol for 6 h/day, 5 days/week, for 13 weeks at gravimetrically determined levels of 24, 70, and 243 mg/m3 resulted in respiratory tract effects (laryngeal) at the highest exposure level with complete recovery within 4 weeks postexposure. The results indicate that the no-observed-adverse-effect level for caprolactam is 70 mg/m3, based on upper respiratory effects, with 243 mg/m3 representing a no-observed-effect level for systemic toxicity, neurotoxicity, and lower respiratory tract effects.

Metabolism of 1,1-dichloro-1-fluoroethane (HCFC-141b) in human volunteers.

Human subjects were exposed by inhalation to 250, 500, and 1000 ppm 1,1-dichloro-1-fluoroethane (HCFC-141b) for 4 hr, and urine samples were collected from 0-4, 4-12, and 12-24 hr for metabolite analysis. 19F nuclear magnetic resonance spectroscopic analysis of urine samples from exposed subjects showed that 2,2-dichloro-2-fluoroethyl glucuronide and dichlorofluoroacetic acid were the major and minor metabolites, respectively, of HCFC-141b. Urinary 2, 2-dichloro-2-fluoroethyl glucuronide was hydrolyzed to 2, 2-dichloro-2-fluoroethanol by incubation with beta-glucuronidase, and the released 2,2-dichloro-2-fluoroethanol was quantified by gas chromatography/mass spectrometry. Concentrations of 2, 2-dichloro-2-fluoroethanol were highest in the urine samples collected 4-12 hr after exposure, but 2,2-dichloro-2-fluoroethanol was also detected in the samples collected 0-4 and 12-24 hr after exposure. Exposure concentration-dependent excretion of 2, 2-dichloro-2-fluoroethanol, obtained by hydrolysis of 2, 2-dichloro-2-fluoroethyl glucuronide, was observed in seven of the eight subjects studied. In conclusion, HCFC-141b is metabolized in human subjects to 2,2-dichloro-2-fluoroethanol, which is conjugated with glucuronic acid and excreted as its glucuronide in urine in a time- and exposure concentration-dependent manner.

Four-week repeated inhalation study of HCFC 225ca and HCFC 225cb in the common marmoset.

Four male and three female marmosets in each group were exposed to air only, 1000 ppm of HCFC 225ca or 5000 ppm of HCFC 225cb, for 6 h per day for 28 consecutive days. HCFC 225ca caused a slight reduction in body weight. HCFC 225cb occasionally caused somnolence during exposure and vomiting on the first day of exposure. Clinical chemistry findings included a mild reduction of triglyceride, cholesterol and phospholipid levels and increased GOT level in the HCFC 225ca exposure group. HCFC 225cb also caused a reduction of triglyceride levels in some animals. HCFC 225ca caused a slight increase of hepatic carnitine palmitoyltransferase (CPT) activity while HCFC 225cb slightly increased cyanide-insensitive palmitoyl CoA beta-oxidation (FAOS) activity. In the HCFC 225cb exposure group, an increase in cytochrome P-450 content was also observed. HCFC 225ca caused a fatty change in the hepatic cells. Increased incidence of lipid droplets in the hepatic cells and myelin-like bodies in hepatic cells, Kupffer's cells and hepatic blood vessels were observed electron microscopically in the HCFC 225ca exposure group. A proliferation of smooth endoplasmic reticulum was observed in the HCFC 225cb exposure group. Decreased peroxisome volume density in the HCFC 225ca group, and increased volume density in the HCFC 225cb exposed females were seen. However, organ weight measurement and histopathological examination did not reveal hepatomegaly or hypertrophy with either substance. Although slight changes were noticed in peroxisome volume density and in some of the peroxisomal enzyme activities, the changes related to peroxisome proliferation with HCFC 225ca and 225cb were minimal in marmosets compared to those seen in rats. Histopathological examination and hormonal analysis did not reveal any abnormalities in the pancreas or testes.

Inhalation teratology and reproduction studies with 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123).

HCFC 123 is one of the chemicals being developed as a replacement for CFC 11 in refrigerant and solvent applications. Supplementing earlier rat teratology studies, a rabbit inhalation teratology study was conducted. In addition, one-generation and two-generation inhalation reproduction studies were conducted. In the teratology study, the pregnant rabbits were exposed to levels of 0 (control), 500, 1500, and 5000 ppm, 6 hr per day from Days 6 through 18 of gestation. Slight body weight losses and reduced food consumption were seen in does in all three exposure level groups. This response followed an exposure-related pattern. There were no other signs of maternal toxicity. There was also no evidence of treatment-related effects on the kits. A probe one-generation reproduction study was conducted. In this study four groups of 12 male and 12 female rats were exposed to vapors of HCFC 123 6 hr per day, 7 days per week from 4 weeks prior to mating through weaning of their offspring. The exposure levels for this study were 0 (control), 300, 1000, and 5000 ppm. There were no effects on mating and fertility, or on pup survival or birth weight. A two-generation study was subsequently conducted. In this study, five groups of 32 male and female rats were exposed to HCFC 123 from 6 weeks of age through weaning. From the offspring of these animals, groups of 28 males and females were selected for the F1 generation. These animals were exposed to HCFC 123 from weaning (4 weeks of age) through weaning of the F1 generation. All exposures were 6 hr per day, 7 days per week. The exposure levels for this study were 0 (control), 30, 100, 300, and 1000 ppm. There were no effects on any of the fertility or reproductive indices measured. As with prior studies, decreases in serum triglyceride levels were seen. Pup survival and birth weight were unaffected by treatment. Pup body weight gain was lower in all treatment groups during nursing, following an exposure-related pattern. Since weight gain for the F1 animals was normal following weaning, this depression of body weight gain may be related to the depression of serum triglycerides. In addition, liver weights of the adult rats exposed to levels of 100 ppm and higher of HCFC 123 were higher than controls, histological examination revealed only hepatic enlargement and vacuolation. It was concluded that exposure to HCFC 123 did not cause reproductive effects although it did effect the body weight gain of the offspring during lactation.

Subchronic toxicity and teratogenicity of 2-chloro-1,1,1,2-tetrafluoroethane (HCFC-124).

Inhalation studies were conducted to determine the potential toxicity of HCFC-124. Groups of rats and mice were exposed to HCFC-124 6 hr/day, 5 days/week for 13 weeks at 0, 5000, 15,000, and 50,000 ppm. Subgroups of rats and mice were held for a 1-month recovery period. A functional observational battery (FOB) was conducted on rats at 0, 4, 13, and 16 weeks. Clinical pathology evaluations were conducted at 7, 13, and 17 weeks. Thirteen or 17 weeks after study initiation, rats and mice underwent gross and microscopic evaluation, and livers were evaluated for hepatic beta-oxidation activity. In addition, groups of female rats and rabbits were exposed to HCFC-124 by inhalation during gestation to 0, 5000, 15,000, or 50,000 ppm. Exposure of rats and mice to HCFC-124 caused minimal compound-related effects. Compound-related changes occurred in several clinical pathology parameters in rats and mice. Hepatic beta-oxidation activity was significantly higher in 5000, 15,000, and 50,000 ppm male mice; however, there were no compound-related effects on beta-oxidation activity in rats. During the daily exposures, rats, mice, and rabbits exposed to 50,000 ppm were less responsive to auditory stimuli or less active compared to controls. At the 13-week FOB, male rats exposed to 15,000 or 50,000 ppm had decreased arousal. There were no compound-related effects on mortality, clinical signs, ocular tissues, hematology parameters, organ weights, and tissue morphology at any concentration in rats or mice. Maternal toxicity in rats was evident by a significant decrease in weight gain and food consumption at 50,000 ppm. Similarly, 50,000 ppm pregnant rabbits had lower food consumption. However, for both rats and rabbits, there was no evidence of fetal toxicity at any concentration.

Acute, subchronic, and developmental toxicity and genotoxicity of 1,1,1-trifluoroethane (HFC-143a).

The toxicity potential of 1,1,1-trifluoroethane (HFC-143a), a CFC alternative, was evaluated in several acute, subchronic, and developmental toxicity studies by the inhalation route and in genotoxicity studies. HFC-143a has a very low acute inhalation toxicity potential as shown by a 4-hr LC50 of > 540,000 ppm in rats. HFC-143A has a low potential to induce cardiac sensitization in experimental screening studies in dogs; only the highest concentration tested--300,000 ppm--elicited a cardiac sensitization response. In an initial 4-week nose-only inhalation study, male and female rats were exposed 6 hr/day, 5 days/week at concentrations of 0, 2000, 10,000, or 40,000 ppm. Females showed no evidence of toxicity at any exposure level; male rats did exhibit degenerative changes only in the tests at all exposure levels. However, because of exposure system irregularities, which resulted in excessive temperature conditions and stress in the HFC-143a-exposed groups, the study was repeated in male rats exposed by whole-body inhalation. In this repeat study no toxicity was observed at < or = 40,000 ppm. Moreover, a subsequent 90-day whole-body inhalation study in rats exposed 6 hr/day, 5 days/week at 0, 2000, 10,000, or 40,000 ppm resulted in no evidence of toxicity at any exposure concentration. The results of the second 4-week and the 90-day studies using whole-body exposures indicate that the findings from the first 4-week study were related to the stress induced by excessive temperatures and nose-only restraint. Therefore, the no-observed-effect level (NOEL) for rats repeatedly exposed up to 90 days was considered to be 40,000 ppm. In developmental toxicity studies with rats and rabbits, an increase in visceral variations or skeletal malformations was observed, respectively, at HFC-143a concentrations of 2000, 10,000 or 40,000 ppm (rat) or at the low and high concentrations (rabbit). Because of the unusually low control incidence of variations (1.6% per litter in the control versus 6.8-16.8% for historical control values), the lack of a clear dose-response relationship, and the lack of other developmental effects, these findings were not considered related to HFC-143a exposure. In addition, results from genotoxicity studies (Ames, chromosomal aberration with human lymphocytes, mouse micronucleus) demonstrated that HFC-143a was not mutagenic.

Topical treatments for hydrofluoric acid dermal burns. Further assessment of efficacy using an experimental piq model.

Several topical treatments for hydrofluoric acid dermal burns (Zephiran, calcium acetate and magnesium hydroxide antacid soaks, and calcium gluconate gel) were assessed for efficacy in a pig model. Gross appearance and histopathology of treated and untreated burn sites were evaluated. For superficial burns, Zephiran was most effective; calcium acetate, magnesium hydroxide antacid, and calcium gluconate gel were less effective. For deep burns, gross observations showed that calcium acetate and Zephiran were most efficacious, whereas histopathology indicated comparable efficacy of Zephiran, calcium acetate, and calcium gluconate gel for all skin layers. Magnesium hydroxide antacid demonstrated efficacy only for the subdermis. The clinically beneficial effects of both Zephiran and calcium gluconate gel were affirmed. Although results suggest that calcium acetate and magnesium-containing antacids may be beneficial for human hydrofluoric acid dermal burns, these are not established clinical treatments.

Toxicological evaluation of 1,1,1,2,2-pentafluoroethane (HFC-125).

Acute, subacute, and subchronic inhalation toxicity studies, developmental toxicity studies, a cardiac sensitization evaluation, and mutagenicity assays were conducted with pentafluoroethane (HFC-125). In the acute study, rats were exposed to a single concentration of 800,000 ppm for 4 hr. Ataxic gait and abnormal respiration were observed during exposure but not after exposure. There was no mortality or other signs of toxicity. Repeated exposures of rats to 50,000 ppm, 6 hr/day, 5 days/week for either 4 or 13 weeks elicited no effects on body weight, food consumption, clinical signs, hematology, biochemistry, urinalysis, organ weight, or tissue morphology. Positive evidence of cardiac sensitization in response to an intravenous epinephrine challenge in dogs was seen at 100,000 ppm and above, but not at 75,000 ppm. HFC-125 was not mutagenic in Salmonella typhimurium and Escherichia coli strains at concentrations of 20 to 100% (v/v) with and without activation. No evidence of clastogenic activity was observed in cultured Chinese hamster ovary (CHO) cells or human lymphocytes at < or = 70% HFC-125 when treatments were conducted for 3-4 hr with activation or for 24 and 48 hr (human lymphocytes only) without activation. However, a statistically significant increase in chromosomally aberrant cells was observed in CHO cells at 60% HFC-125 when treatment without activation was extended to 48 hr. The biological significance of this effect is questionable since signs of severe toxicity were also present. In vivo, no micronuclei were induced in mouse bone marrow at concentrations as high as 600,000 ppm HFC-125 for a 6-hr exposure. In addition, HFC-125 did not induce embryotoxic or teratogenic effects in either the rat or the rabbit at exposure concentrations as high as 50,000 ppm.

Acute and subchronic toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b).

The acute and subchronic toxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b), a CFC alternative, was evaluated in several acute and subchronic studies to assist in establishing proper handling guides. Data from acute toxicity studies in rats and rabbits demonstrated that HCFC-141b has very low acute toxicity. HCFC-141b was not a skin irritant, but was a mild eye irritant, in rabbits and was not a skin sensitizer in guinea pigs. Skin application of HCFC-141b to rabbits at 2000 mg/kg body weight produced no adverse effects. Oral administration at 5000 mg/kg body weight did not cause any deaths or clinical signs of toxicity in rats. The 4-hr LC50 for HCFC-141b was about 62,000 ppm in rats. Repeated exposures of rats for 6 hr/day, 5 days/wk for up to 90 days at concentrations of 2000, 8000 or 20,000 ppm did not result in significant adverse effects. Minor, but dose-dependent, reductions in body weight were observed in male and female rats during the 90-day study. Decreased responsiveness was also observed in rats but only at 20,000 ppm. An increase in serum cholesterol or triglycerides was observed in male and female rats at 20,000 ppm, and in males at 8000 ppm. No specific organ pathology was noted in these subchronic inhalation studies. The no-observable-adverse-effect level (NOAEL) from these studies was 8000 ppm. Results from other studies demonstrate that HCFC-141b was not neurotoxic in rats. As with trichlorofluoroethane (CFC-11), a cardiac sensitization response to an intravenous epinephrine challenge occurred in dogs with HCFC-141b at 5000 ppm and higher concentrations in experimental screening studies.

1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo.

Subchronic and chronic studies were carried out in the rat and a developmental toxicity study in the rabbit with exposures to 1,1,1,2-tetrafluoroethane (HFC 134a) by inhalation. In the rat repeated exposure to 50,000 ppm HFC 134a for 13, 52, and 104 weeks elicited no effect on clinical condition, growth, and survival, or on a variety of hematological, clinical chemistry, and urinary parameters. Treatment-related pathological changes were seen only at study termination at 2 years and were confined to increased incidence of Leydig cell hyperplasia and adenoma in male rats exposed to 50,000 ppm. The tumors, which were also seen in control animals, were benign and not life-threatening. A battery of in vitro and in vivo tests gave no evidence of genotoxic activity. With exposure to pregnant rabbits, the only treatment-related effects were of minimal maternal toxicity at high exposure concentrations; there were no effects on fetal development. It is concluded that HFC 134a is of very low toxicity and should be an acceptable alternative to CFCs.

Two-year inhalation toxicity study in rats with hydrochlorofluorocarbon 123.

The potential chronic toxicity and oncogenicity of hydrochlorofluorocarbon 123 (HCFC-123) was evaluated by exposing male and female rats to 0, 300, 1000, or 5000 ppm HCFC-123 for 6 hr/day, 5 days/week, for 2 years. Clinical pathology was evaluated at 6, 12, 18, and 24 months. An interim termination and measurements of hepatic cell proliferation and beta-oxidation activity were conducted at 12 months. The terminal euthanization occurred at 24 months. Males and females exposed to 5000 ppm and females exposed to 300 or 1000 ppm had lower body weights and body weight gains. Serum triglyceride and glucose concentrations were significantly decreased at all exposure concentrations in both sexes. Serum cholesterol was also lower in 300, 1000, and 5000 ppm females and in 5000 ppm males. Alterations in serum protein concentrations occurred at 300, 1000, and 5000 ppm. Survival was higher in 1000 and 5000 ppm males and females. At 24 months, increased relative liver weight occurred in 5000 ppm males, and decreased absolute kidney weight occurred in 5000 ppm males and in 1000 and 5000 ppm females. Benign hepatocellular adenomas were increased in 5000 ppm males and in all test groups of females. Hepatic cholangiofibromas were also increased in 5000 ppm females. Pancreatic acinar cell adenomas were increased in all test groups of males, and acinar cell hyperplasia was increased in the 1000 and 5000 ppm males and females. Benign testicular interstitial adenomas and focal interstitial cell hyperplasia were also increased in all male test groups compared to controls. Diffuse retinal atrophy was increased in all male and female test groups, but it was considered to be an indirect compound-related effect. Hepatic beta-oxidation activity (peroxisome proliferation) was higher in 300, 1000 and 5000 ppm males and 1000 and 5000 ppm females. Compound-related differences in the rate of hepatic cell proliferation were not observed at any exposure concentration. Decreased incidences of a variety of age-related lesions occurred at 1000 and 5000 ppm.