Norflurane

Carcinogenicity

Description of key information

It is considered that 1,1,1,2-tetrafluoroethane (HFC 134a) does not present a carcinogenic risk to  humans at any forseeable level of exposure.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion

Dose descriptor:

NOAEC

208 000 mg/m³

Justification for classification or non-classification

Benign tumours of the testicular interstitial cells (Leydig cell adenoma) are common in the ageing rat. The spontaneous incidence of this tumour type is variable from one strain to another, ranging from a few percent in Sprague-Dawley rats up to 100% in some Wistar-derived and Fisher 344 rats (Bär, 1992). These tumours do not usually progress to malignancy in the rat (e.g. no malignant Leydig cells tumours found in several thousands of control Fisher rats) (Boorman et at, 1990; Iawata et al, 1991). An increased incidence of Leydig cell tumours has been described following exposure to a large number of substances covering a wide variety of chemical structures e.g. isradipine (Roberts et al, 1989), mesulargine (Prentice et al, 1992), cimetidine (Leslie et al, 1981), hydralazine, carbamazepine (Griffith, 1988) and even such a common dietary component as lactose (Bär, 1992). Leydig cell tumours are known to secrete sex hormones (e.g. testosterone, dihydroandosterone, oestradiol) and it is thought that the high incidence of hyperplasia and tumours of the Leydig cell in aging rats is related to senile endocrine disturbance (Mostofi and Price, 1973). HFC-134a induced Leydig cell hyperplasia and tumours in the rat occurred late in life and were not associated with increased mortality. HFC-134a (like many other known Leydig cell carcinogens), is not mutagenic. Consequently, the increased incidence of Leydig cell tumours observed in rats exposed to HFC-134a is attributable to a non-genotoxic mechanism. Non-genotoxic mechanisms have been frequently associated with hormonal imbalances, especially an imbalance of sex hormones (Neumann, 1991). The observation that exposure to HFC-134a can reduce the stimulatory effects of MIT on prolactin secretion and causes a marked reduction in testicular testosterone levels suggests that a hormonal mechanism might be responsible for the increase incidence of Leydig cell tumours, possibly by increased feedback of Leydig cell production and secretion of testosterone in response to the decreased tissue levels of the hormone. In addition, HFC-134a has a significant effect on pituitary gonadotropin secretion (augmented FSH release) and hormone content (decreased LH-FSH content, augmented prolactin content in the rat). The changes are of sufficient magnitude to explain changes in Leydig cell function which could ultimately after long term exposure result in Leydig cell hyperplasia. Such endocrine changes are of a reversible nature if the period of exposure in rats is limited. In long term toxicology studies the present findings would be compatible with the late onset of Leydig cell hyperplasia as a reaction to functional changes in the secretion of LH, FSH and prolactin in the rat. The consequences of this finding for humans are considered to be biologically and toxicologically irrelevant. Moreover, in contrast to the rat, the incidence of Leydig cell tumours in humans is extremely low, representing less than 3% of all testicular neoplasms (Mostofi and Price, 1973). The rarity of Leydig cell tumours in man, compared to the high spontaneous incidence in the rat, demonstrate that these tumours are not relevant to humans. Consequently the increased frequency of the benign Leydig cell tumours observed in rats exposed to HFC-134a at the high concentration of 50,000 ppm (208,000 mg/m3) is considered not to indicate a tumorigenic risk to humans, and classification as a carcinogen is not warranted according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

Two carcinogenicity studies were conducted. In a limited study (52 weeks of treatment) in rats with daily oral administration (in corn oil) of 300mg HFC 134a / kg.bw, no tumorigenic effect was seen during the 16 month post treatment observation period.

In the key study, daily inhalation exposures of up to 50000ppm (208000 mg/m3) for 104 weeks did not produce neoplastic changes in female rats. In male rats exposed to 50000ppm, slight increases in the incidence of testicular Leydig cell hyperplasia and benign Leydig cell adenomas were observed. As HFC 134a is not genotoxic, these changes are most likely to be due to a non-genotoxic, hormonally-based mechanism, e.g. due to an effect on pituitary function and to prolactin secretion and of no significance to for humans. Therefore, it is considered that HFC 134a does not present a carcinogenic risk to humans at any forseeable levels of exposure.

Update October 2011

Following a further review of the data, the Registrant has not changed its conclusion that 50,000 ppm is the NOAEC for the carcinogenic effects of HFC134a. This conclusion is drawn from the results of a single informative study that is judged to be Reliability 1.

Rats were exposed for 6 hours/day, 5 days per week for 2 years to concentrations of HFC134a up to 50,000 ppm. An increased incidence of Leydig cell hyperplasia and benign Leydig cell tumours were seen in rats exposed to 50,000 ppm. The NOEC of HFC134a for carcinogenic effects in the rat in this study was 10,000 ppm (Hext et al, 1993).Benign tumours of the testicular interstitial cells (Leydig cell adenoma) are common in the ageing rat. The spontaneous incidence of this tumour type is variable from one strain to another, ranging from a few percent in Sprague-Dawley rats up to 100% in some Wistar-derived and Fisher 344 rats (Bär, 1992). These tumours do not usually progress to malignancy in the rat (e. g. no malignant Leydig cells tumours found in several thousands of control Fisher rats) (Boorman et at, 1990; Iawata et al, 1991). An increased incidence of Leydig cell tumours has been described following exposure to a large number of substances covering a wide variety of chemical structures e. g. isradipine (Roberts et al, 1989), mesulargine (Prentice et al, 1992), cimetidine (Leslie et al, 1981), hydralazine, carbamazepine (Griffith, 1988) and even such a common dietary component as lactose (Bär, 1992). Leydig cell tumours are known to secrete sex hormones (e. g. testosterone, dihydroandosterone, oestradiol) and it is thought that the high incidence of hyperplasia and tumours of the Leydig cell in aging rats is related to senile endocrine disturbance (Mostofi and Price, 1973).HFC134a-inducedLeydig cell hyperplasia and tumours in the rat occurred late in life and were not associated with increased mortality. Since HFC134a is not mutagenic, the increased incidence of Leydig cell tumours observed in rats exposed to HFC134a is attributable to a non-genotoxic mechanism. Non-genotoxic mechanisms have been frequently associated with hormonal imbalances, especially an imbalance of sex hormones (Neumann, 1991). The observation that exposure to HFC134a can reduce the stimulatory effects of MIT on prolactin secretion and causes a marked reduction in testicular testosterone levels suggests that a hormonal mechanism might be responsible for the increase incidence of Leydig cell tumours, possibly by increased feedback of Leydig cell production and secretion of testosterone in response to the decreased tissue levels of the hormone. In addition, HFC134a has a significant effect on pituitary gonadotropin secretion (augmented FSH release) and hormone content (decreased LH-FSH content, augmented prolactin content in the rat). The changes are of sufficient magnitude to explain changes in Leydig cell function which could ultimately after long term exposure result in Leydig cell hyperplasia. Such endocrine changes are of a reversible nature if the period of exposure in rats is limited. In long term toxicology studies the present findings would be compatible with the late onset of Leydig cell hyperplasia as a reaction to functional changes in the secretion of LH, FSH and prolactin in the rat. The consequences of this finding for humans are considered to be biologically and toxicologically irrelevant. Moreover, in contrast to the rat, the incidence of Leydig cell tumours in humans is extremely low, representing less than 3% of all testicular neoplasms (Mostofi and Price, 1973). The rarity of Leydig cell tumours in man, compared to the high spontaneous incidence in the rat, demonstrate that these tumours are not relevant to humans. Consequently, the increased frequency of the benign Leydig cell tumours observed in rats exposed to HFC134a at the high concentration of 50,000 ppm (208,000 mg/m3) is considerednot to indicate a carcinogenic hazard to humans.

It is concluded, therefore, that these findings need not be taken into account when considering the point of departure for the derivation of the DNELfor HFC134a.