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

Carcinogenicity

Justification for classification or non-classification

The 2-year combined chronic toxicity/carcinogenicity study with HCFC-123 in rats has shown increased incidences of liver, pancreatic and testis tumours. It is noted that these tumours were all benign, appeared late in life (primarily in males) and were not life threatening to the animals. In fact, animals in the high-exposure groups had a statistically significant increase in survival at 2 years compared to controls. Because HCFC-123 was assessed as non-genotoxic (Section 7.6), the tumours appear to be epigenetic in origin. The formation of hepatic tumours can be linked with the rodent-specific peroxisome proliferation potential of HCFC-123, while the testicular tumours may have resulted from enhanced hormonal disturbances in senescent rats. Thus, the hepatic and Leydig cell adenomas are considered of no or doubtful relevance for human health hazard assessment. The mechanism of benign pancreatic acinar cell adenoma is not understood, and the significance of these tumours for humans remains uncertain.

Overall the weight of evidence indicates that no classification of HCFC 123 as a carcinogen is warranted in accordance with EU Directive 67/548/EEC and Regulation (EC) No. 1272/2008.

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 focal 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 (hepatic adenomas) were associated to the induced hepatic peroxisome proliferation and considered of no relevance to humans. A small increase in incidence of benign hepatocholangio-fibroma was observed in females exposed at the highest concentration only. Although benign hepatocolangio-fibromas were observed in combination with hepatocellular tumours in few peroxisome proliferators, most peroxisome proliferations do not give rise to this tumour type and thus peroxisome proliferation does not appear as an obvious hypothesis for the increase of cholangio-fibroma. Similarly, the assessment of the benign testes adenomas led to conclusion of low relevance to humans: Leydig cell tumors in rodents may infact be caused by hepatic peroxisomal proliferation. Moreover, benign tumours of the testicular interstitial cells are common in the aging rat, likely due to hormonal unbalances occurring during the senescence process. Overall, the increased frequency of benign Leydig cell tumours in rats exposed to HCFC-123 is not likely to be indicative of a tumourigenic hazard to humans. The incidence of benign pancreatic acinar cell adenoma was increased in a dose-dependent pattern in all male groups exposed to HCFC 123. Although not statistically significant, increased incidence of this tumour was also seen in females exposed at 300 and 5,000 ppm, but not at 1,000 ppm. The incidence was lower in females compared to males. Also increased was the incidence of acinar cell hyperplasia, which is considered the precursor to the adenoma. It is interesting to note that some peroxisome proliferators inducing rat hepatocellular and Leydig cell adenomas also induced pancreatic acinar cell tumours. Hypotheses have been formulated to establish a causal relationship between the pancreatic acinar cell tumours and the hepatic PPRA-alpha activation, however the mode of action is not yet understood. 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).