Theophylline

Endpoint summary

Description of key information

Oral: LD50 = 272 mg/kg bw, (rat, comparable to OECD 401; BASF AG 1983). 
Inhalation: LC50 > 6.7 mg/L dust (rat, 4 hours, according to OECD 403; BASF AG 1989). 
Dermal: LD50 > 2000 mg/kg bw (rat, comparable to OECD 402; BASF AG 1988).
The test compound is of moderate toxicity after single ingestion and of low toxicity after inhalation and a single skin contact.    

Additional information

There are valid data available for the assessment of the acute oral, inhalative and dermal toxicity of theophylline.

Oral

In an acute toxicity study conducted by Knoll AG/BASF AG (1983) according to a protocol similar to OECD 401, doses of 100 - 1000 mg/kg bw were administed to 10 Sprague-Dawley rats per group and per sex. The animals were observed for 14 days for lethality and clinical signs of intoxication. The LD50 is 272 mg/kg bw for males and females. Mortality and clinical signs such as increased respiratory frequency and eyelid closure appeared as from the dose of 215 mg/kg bw. In the high dose group, more severe clinical symptoms of toxicity such as clonic convulsions, accelerated respiration and salivation were observed. At necropsy anaemia and unspecific bleeding in the thymus was found. Higher doses can be tolerated when the substance is not given as a bolus.

Other acute oral LD50 levels in rat (225 mg/kg bw), guinea pig (183 mg/kg bw), rabbit (350 mg/kg bw) and mouse (235 mg/kg bw) were published in literature without additional data (NIOSH, 1994, RTECS XH3850000).

Additionally, in mice a LD50 of 332 mg/kg bw was observed and clinical signs were convulsions, profuse salivation and emesis was observed (Tarka, 1982, Crit. Rev. Toxicol., 9, 275 -312).

Inhalation

In an acute inhalation study conducted according to a protocol similar to OECD 403, groups of 5 Wistar rats per sex were treated by nose/head exposure to dust aerosol at concentrations of 2.39 and 6.7 mg/L (analytical) for 4 hours and observed for 14 days (BASF AG 1989). No mortality was observed. Clinical signs of toxicity included changes in respiration, such as irregular and accelerated respriration, gasping, as well as salivation and restlessness. No pathologic findings were noted with necropsy. The LC 50 value for dust aerosol was > 6 .7 mg/L.

Another acute inhalative study reported a LC50 in rats of < 36 mg/m³ after 4 hours exposure (Izmerov et al., 1982, Centre of International Projects, GKNT, Moscow; cited in Umweltforschungsplan des Bundesministers fuer Umwelt, Naturschutz und Reaktorsicherheit 1996).

Dermal

A 50 % solution of theophylline in olive oil was applied for 24 hours to the intact skin of Wistar rats (5 animals/sex/dose) under semiocclusive conditions. The observation period following administration was 14 days.

The LD50 for the dermal application was >2000 mg/kg bw. No mortality, no clinical symptoms, no alteration of body weight and no pathological findings in necropsied animals were observed (BASF AG 1988).

In humans mild signs of toxicity are headache, gastrointestinal disturbances, hypotension, irritability and insomnia. Severe symptoms imply tachycardia , arrhythmia, cardiac arrest, convulsions and serious neurological symptoms. Seizures and death have also occurred (IARC 1991; Stavric 1988, Food Chem. Toxicol., 26, 541-565; Ogilvie 1978, Clin. Pharmacokinet., 3, 267-293; Minton N.A. and Henry J.A. 1996, Human and Experimental Toxicology, 15, 471 -481; Winek C.L. et al., 1980, Forensic Sci. Int., 15, 233-236; Parr M.J. et al., 1990, Intesiv. Care Med., 16, 394 -398; Greenberg A. et al., 1984, Am. J. Med., 76, 854-860). Toxicity may be developed at serum levels of 20 -30 μg/ml, whereas at levels below 15 μg/ml generally no symptoms were observed (see Chapter 7.10.3).

Conclusion: In animal studies theophylline showed a high toxicity after oral uptake and a low acute toxicity after dermal and inhalative uptake. In humans adverse effects have been obsered after intentional overdosing. Thereby, theophylline toxicity principally affects the gastrointestinal, cardiovascular and central nervaus systems.

Justification for classification or non-classification

Based on the oral LD50 of ca. 272 mg/kg bw. for rats theophylline has to be classified "Xn, R22" (Harmfull if swallowed) according to EU Annex VI of directive 67/548/EEC and "Category 3" according to GHS classification for the oral route.

Based on the inhalative LC50 > 6.7 mg/L dust and on the dermal LD50 > 2000mg/kg bw., theophylline has not to be classified according to EU and GHS requirements for the inhalative (dust aerosol) and dermal route.