2,2-dichloro-1,1,1-trifluoroethane

Endpoint summary

Description of key information

Several repeated inhalation toxicity studies were carried out  

Additional information

HCFC-123 was tested in a combined chronic toxicity-oncogenicity study in rats (Haskell, 1992). Male and female rats were exposed by inhalation to 300, 1000 and 5000 ppm HCFC-123 for approximately two years. Several significant compound-related changes were observed at the study termination and during the interim examinations performed at 6, 12 and 18 months. Serum triglyceride and glucose concentrations were significantly decreased compared to control values at all exposure concentrations, and in both sexes. Serum cholesterol was also significantly lower in females exposed to 300, 1,000, or 5,000 ppm and in males exposed to 5,000 ppm. In addition, male and female rats exposed to 5,000 ppm and females exposed to 1,000 ppm had lower body weight and body weight gain. Females exposed to 1,000 ppm or 5,000 ppm also had significantly greater survival, and 1,000 and 5,000 ppm males had slightly greater survival compared to controls. The increased survival can be attributed to the beneficial effects of lower body weight and serum triglycerides/lipids.

At the 24-month sacrifice, there were compound-related increases in incidences of benign hepatocellular adenomas in 5,000 ppm dose males and in all test groups of females, in benign hepatic cholangiofibromas in 5,000 ppm females, in benign pancreatic acinar cell adenomas in all test groups of males, and in benign testicular tumors in all test groups of males. Acinar cell hyperplasia of the pancreas was increased in the 1,000 and 5,000 ppm males and females. Since pancreatic acinar cell adenomas are a continuum of acinar cell hyperplasia, the incidence of acinar cell adenomas and hyperplasia in all test groups of females is also considered to be compound related. Several non neoplastic changes were observed in the liver, including increased incidence of cellular alteration (basophilic) in all test groups of males and females, treatment-related increased incidence in hepatic focal necrosis in males, increased incidence of sinusoidal ectasia in females at 5000 ppm, increased incidence of hepatic cystic degeneration in males exposed to

1000 and 5000 ppm and females at 5000 pm and hepatic centrilobular fatty change was observed in both sexes at 5000 ppm. Higher hepatic Beta-oxidation activity, indicating an induction of hepatic peroxisome proliferation, was observed in both sexes of exposed groups in comparison to controls. Hepatic cell proliferation may accompany an increase in hepatic Beta-oxidation activity; however, a sustained increase in cell proliferation was not evident at the 12 -month interim sacrifice at any exposure concentration. A no-observable-effect level was not achieved for this study based on the effects in clinical chemistry parameters at all concentrations, lower body weight and body weight gain at 300, 1,000, and 5,000 ppm, organ weight changes at 5,000 ppm, increased incidence of neoplastic and non-neoplastic morphological changes, and higher hepatic peroxisomal Beta-oxidation activity at all concentrations. The neoplastic changes observed in liver, testes and pancreas were associated to the induced hepatic peroxisome proliferation and considered of no or doubtful relevance to humans. A full assessment of those tumours is reported in the Joint Assessment on Commodity Chemicals no. 47 (ECETOC, 2005) and in the Workplace Environmental Exposure Level Guide for HCFC 123 (WEEL Guide, American Industrial Hygiene Association, 1998)..

Several subchronic toxicity studies were carried out (Haskell 1990 and ECETOC 2005).

In one study (Haskell, 1990), groups of 10 Sprague-Dawley rats/sex/group were exposed (6 h/d, 5 d/wk) by inhalation to HCFC-123 at concentrations of 0, 300, 1,000, 5,000 ppm (1,880, 6,250 or 31,300 mg/m3) for 90 days. Rats exposed at 31,300 mg/m3 showed slight anaesthetic effects. At this same concentration, as well as at 1,000 ppm, decreased body weight gain was observed. Except for slightly elevated urinary fluoride levels in males at 5,000 ppm, and in all female groups, no other effects relating to haematology or urinary analysis were noted. Serum triglyceride and glucose levels were reduced in both sexes at all levels of exposure. Serum cholesterol was also reduced in female rats at 1,000 and 5,000 ppm. At the 90-day terminal sacrifice, slightly increased liver weights were observed at the two highest exposure concentrations. However, no histopathological effects were noted at any exposure level. Hepatic peroxisome β-oxidation activity to palmitoyl-CoA oxidase was increased in rats in all exposure groups. Comparison of liver sections from the control and high-exposure group by electron microscopy revealed a 2- to 3-fold increase in peroxisome number in the high dose animals. 2 other studies are reported in the Joint Assessment on Commodity Chemicals no 47 (ECETOC, 2005). In one groups of 35 male and 25 female Sprague-Dawley rats were exposed to vapours of HCFC-123. Twenty-five male and 20 female rats in each group were sacrificed following the final exposure. The remaining 10 males and 5 females were held an additional 30 days and then sacrificed. The target levels for this study were 0 (control), 500, 1,000 or 5,000 ppm (0, 3,130, 6,250 or 31,300 mg/m3). No treatment-related deaths occurred in this study and mean body weight reductions observed in high dosed males and the two highest dosed groups of females were significant only at the week 13 interval. Slight depressions were observed in heart weight in both male and female rats exposed to 1,000 ppm HCFC-123. While depressions in kidney weights and kidney/brain weight ratios, but not kidney/body weight ratios, were observed in male rats in all 3 exposure groups, these effects appeared to be biologically significant only in the 5,000 ppm exposure group. A depression in kidney weight and kidney/body weight ratio, but not in kidney/brain weight ratio, occurred in the 5,000 ppm exposed females. Increased liver/body weight ratios, but not liver weight or liver/brain weight ratios, were observed in the 5,000 ppm exposed males and in all 3 female exposure groups. However, no significant differences were found for absolute or relative organ weights in animals sacrificed at the end of the 30-day recovery period. The absence of histopathological findings coupled with the absence of effects at the end of the recovery period suggest these effects to be of marginal significance, if at all, in relation to the HCFC-123 exposure.

In another study, Sprague-Dawley rats (27/sex/group) and 4 male Beagle dogs were exposed (6 h/d, 5 d/wk) by inhalation to HCFC-123 at concentrations of 0, 1,000 or 10,000 (0, 6,250 or 62,500 mg/m3) for 90 days. At the high dose level, both species exhibited lack of motor co-ordination soon after the start of exposure. This was followed by reduced motor activity and a reduction in responsiveness to noise. After removal from exposure, co-ordination and activity returned to normal within 20 minutes. In rats, there were no adverse effects other than a reduction of final body weight, increase in relative liver weight and elevated urinary fluoride concentration at the two test levels. At the high concentration level, dogs exhibited histopathological changes in the liver characterised by hypertrophy, clear cytoplasm and necrosis of liver cells with inflammatory infiltration and clinical chemistry changes. These changes included increased levels of serum and liver alkaline phosphatase, ALT and AST, indicative of slight liver damage. No compound-related effects were noted at the lower (1,000 ppm) exposure level.

Similar effects to those observed in the subchronic studies were found in a 4 -week study in rats (Haskell, 1989).

Kabe et al. (2001) tested HCFC 123 in guinea pigs for 4 -weeks by inhalation.Groups of eight male Hartley guinea pigs were exposed to 30, 100 or 300 ppm 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123) by inhalation for 6 hours a day for 4 wk. Guinea pigs exposed to 300 ppm HCFC-123 had significantly lower body weight and the weight gain than controls, but there was no significant difference and no tendency in absolute and relative organ weight. In the 100 ppm group, a few vacuolar fatty changes in the portal area (zone I) were identified. In the 300 ppm group, severe fatty degeneration was observed in the portal and intermediate areas, partly centrilobule, and the incidence increased significantly compared to the controls. On the other hand, there was no histopathological change in the control or 30 ppm groups. No increase in any of the liver peroxisomal enzymes (AOX, PT, catalase) was seen in male guinea pigs exposed to HCFC-123. The activity of hepatic ALDH was significantly decreased in the 300 ppm exposed group, suggesting that HCFC-123 or its metabolite inhibited ALDH activity.

Liver effects were also observed in 4 lactating female Rhesus monkeys exposed for 6 h/day, 7 days/week for 3 weeks to air or 1000 ppm HCFC-123 (Cappon et al., 2002). Exposure of monkeys to 1000 ppm HCFC-123 did not result in exposure-related clinical observations, or changes in body weight, appetence and behavior. There were no exposure-related effects on serum triglycerides, cholesterol, or glucose levels. Liver microsomal P450 and peroxisome oxidase activities showed exposure-related decreases in CYP4A1 and CYP2E1 and acyl-CoA oxidase for animals exposed to HCFC-123. Microscopic evaluation of maternal liver from HCFC-123 exposed animals revealed mild to moderate centrilobular hepatocyte vacuolation, trace to mild centrilobular necrosis, and trace to mild subacute inflammation. The histopathological damage and altered hepatic biochemical activities produced by HCFC 123 in monkeys are not consistent with the HCFC 123 peroxisome proliferation response observed in rat livers.

Finally, 2 subacute studies were performed to confirm the hepatic peroxisome proliferation to be the active mode of action in rats (Haskell 1992 and Central Toxicology Laboratory, 1990). Both studies showed a good correlation between the effects in the rat liver and the induction of hepatic peroxisome proliferation in rats exposed to HCFC 123. Furthermore, a comparison between rats and guinea pigs (Haskell, 1992) demonstrated that hepatotoxicity induced by HCFC 123 is likely mediated by different mode of action in the 2 species and that guinea pigs are likely more sensitive than rats to the substance.

Justification for classification or non-classification

Liver toxicity was observed in different species following repeated exposure by inhalation. The hepatotoxicity observed in rats is likely mediated by increased induction of hepatic peroxisome proliferation, a known mode of action of no relevance to humans. However, liver toxicity was observed also in species in which peroxisome proliferation is likely not the active mode of action.

Namely, liver toxicity was observed in monkeys (20 day-NOAEC < 1000 ppm), guinea pigs (28 day NOAEC = 30 ppm) and dogs (90 day-NOAEC 1000 ppm). Furthermore, available human data (accident reports, exposure data not available or not reliable, see section 7.10.5) indicate possible occurrence of liver toxicity following repeated exposure to HCFC 123. Overall, the weight of evidence indicates the needs to classify HCFC 123 as harmful danger of serious damage to health by prolonged exposure through inhalation (Xn R48/20) under EU Directive 67/548/EEC and STOT RE Cat. 2 (H373) under Regulation (EC) No. 1272/2008