Theophylline

Carcinogenicity

Description of key information

In the long-term studies in rats and mice in which the substance was given by gavage, a carcinogenic effect was not observed. 
Rat, gavage, 2 years: no carcinogenicity (Nyska et al., 1998; NTP 1998)
Mouse, gavage, 2 years: no carconogenicity (NTP 1998)

Justification for classification or non-classification

From the available data, there is no indication given for a carcinogenic potential of theophylline. Therefore, the substance has not to be classified according to requirements of the EU, Annex VI of Directive 67/548/EEC and of GHS.

Additional information

In a 2 year study, Fischer 344 rats (males and females, 50 animals per sex) were treated by gavage of theophylline in corn oil. The rats were given 0; 7.5; 25 and 75 mg/kg bw/day 5 days a week. There were no significant differences in mortality between control and dosed groups. No clinical findings were attributed to theophylline treatment. Histopathological, an increased incidence of periarteritis was found in high-dose males, which is considered as rat- specific response to vasodilators (OECD SIDS 2004). No significantly increased incidences of neoplasms were found in the treated rats. There were dose-related negative trends in the incidences of mammary gland fibro-adenoma and fibro adenoma or carcinoma (combined) in females; and the incidences in the mid and high-dose females were significantly lower than those in the control group. According to the authors, these differences correlated with decreased body weights.

There was no evidence of carcinogenic activity related to theophylline administration (Nyska A. et al. 1998, Arch. Toxicol. 72, 731 -737; NTP 1998).

 

In a further 2 -year gavage study, B6C3F1 mice were exposed 5 days a week to 15, 50 and 150 mg/kg bw/day in males and to 7.5; 25; 75 mg/kg bw/day in females. Mortality was increased in high-dose males. Body weights were reduced in high-dose males and females and in mid-dose females. No significantly increased incidences of neoplasms or non-neoplastic lesions were found in the treated mice. Decreased incidences of hepatocellular adenomas and hepatocellular adenomas or carcinomas (combined) were found in the treated mice. According to the authors, increases in the incidences of hepatocellular neoplasms in male mice had been shown to be associated with Helicobacter hepaticus infection when hepatitis was also present. Additionally, in the livers of male mice increased incidences of hemangiosarcoma were observed in studies with Helicobacter-associated hepatitis. Thus, interpretation of the decreased incidences of liver neoplasms was difficult. Incidences of lesions at other sites observed in this study were not considered to be significantly impacted by Helicobacter hepaticus infection or its associated hepatitis.

There was no evidence of carcinogenic activity related to theophylline administration (NTP 1998).

No data in humans on the carcinogenicity of theophylline per se are available. Case-control studies did not show an association between total methylxanthine intake and breast cancer (Lubin, F. et al., 1985, JNCI 74, 569 -573; Schairer, C. et al. 1987, Int. J. Cancer 40, 469 -473; Rohan, T.E. and McMichael, A.J. 1988, Int.J.Cancer 41,390 -393; see Chapter 7.10.3).

Conclusion:

Theophylline showed no carcinogenic activity in rats and mice up to the highest dose tested (75 mg/kg bw/d in rats and female mice and up to 150 mg/kg bw/d in male mice). In humans, case-control studies did not show an association between total methylxanthine intake and breast cancer.