Theophylline

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.54 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

12

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.4 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

12

Modified dose descriptor starting point:

LOAEC

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

5

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

Inhalation

Longterm systemic

There were no data for longterm inhalation study. Therefore, an oral, two years repeated dose study was used for calculation. For rats treated in repeated dose studies an increased incidence of periarteritis in males was observed which may be a rat- specific response to vasodilators. According to Nyska et al. (1998) theophylline may cause excessive vasodilatation and the mesenteric and pancreatic arteries in rats may be particularly sensitive to the excessive vasodilator-pharmacological activity of theophylline. Similar to other vasodilatory chemicals (Hanton et al., 1995), the periarteritis caused by theophylline may be a consequence of hemodynamic changes induced in the vascular wall (Nyska et al., 1998).

Therefore, for calculation of the systemic longterm DNEL, a 2-year bioassay with the mouse was used. Here, the substance was administered by gavage to B6C3F1 mice (50 animals per sex). The male mice received 0, 15, 50, and 150 mg/kg bw/d and female mice 0, 7 .5, 25, and 75 mg/kg bw/d (NTP, 1998). In mice, mortality was increased in high-dose males. Body weights were reduced in high-dose males and females and in mid-dose females. Based on the reduced body weight and mortality the NOAEL for males was 50 mg/kg bw/day and based on the reduced body weight, the NOAEL for females was 7.5 mg/kg bw/day.

For DNEL calculation, the NOAEL of 7.5 mg/kg bw/day was used. For inhalation the corrected starting point was calculated as 6.79 mg/m³/ for workers. Therefor, the NOAEL oral, mouse of 7.5 mg/kg bw was multiplicated with 1/0.74 m³/kg/8h, whereas 0.74 m³/kg/8h was calulated from the relative respiratory minute volume from the mouse of 1.533 L/min/kg, by calculating it for 8 hours. Further correction was performed for respiratory volume of workers (10 m³) compared to standard respiratory volume of 6.7 m³. Furthermore, general assessment factores (AF), such as remaining differences (AF = 2.5), intraspecies differences worker (AF = 5) and exposure duration (AF = 1) were used, leading to an overall AF of 12.5. A DNEL for longterm systemic exposure of 0.54 mg/m³ was calculated.

Acute systemic

For the DNEL acute systemic effects an acute inhalation study (adverse effects: accelerated and intermittent respiration) is available.

Groups of 5 Wistar rats per sex were treated by nose/head exposure to dust aerosol at two different concentrations for 4 hours and were observed for 14 days (BASF AG 1989). A systemic LOAEC of 2390 mg/m³ was determined. Due to the low therapeutic index of theophylline a steep dose response curve is expected. Additionally, reduced clinical parameter recording has to be included. Therefore an assessment factor of 10 was used to calculate the NOAEC of 239 mg/m³. As corrected starting point 160.1 mg/m³/day for workers was determined. Thereby, the NOAEC of 239 mg/m³ was corrected to 10 m³ respiration rate for worker compared to 6.7 m³ standard respiration rate. Using the overall AF of 12.5 for worker (calculated using AFs for remaining differences of 2.5 and intraspecies differences of 5 for worker), the systemic acute DNEL for worker was determined as 12.8 mg/m³.

Local long-term and acute

Local long term and acute DNELs for inhalation exposure could not be determined, since no effects were observed. 

 

Dermal

Longterm systemic

For the determination of the dermal DNEL, the NOAEL of 7.5 mg/kg bw/day of the2-year bioassay with the mouse was used. The absorption difference was calculated using the software On-Line EPI Suite™ (v4.0; US EPA). Using the water solubility of 0.0055 mg/cm³, the Log P_owof 0.0076 and DERMWIN (v1.43a 2008 US EPA) of EPI Suite, the dermal absorbed dose per event (DA) was calculated as 2.1e-007 mg/cm². According to Danish EPA (2005), DA < 0.001 is classified as very low and a maximal resorption of 10 % is estimated resulting in an AF of 0.1 for the adsorption difference for oral to dermal extrapolation.

Using this AF for adsorption difference and the AF for intraspecies difference of 5 for workers a dermal DNEL for longterm systemic exposure of 1.5 mg/kg bw/d for worker was calculated.

Acute systemic

An acute systemic DNEL for dermal exposure could not be determined, since no effects were observed (LD50 > 2000 mg/kg).

Local acute

A local acute DNEL for dermal exposure could not be determined. With the skin irritation study, 4 hours after removal of the test substance an erythema score of 1 (very slight reddening) was determined in two females; in one male no effects were observed. No other signs of irritation were noted. DNELs for irritation/corrosion can only be derived if dose-response information is available. There is no information available achieving this requirements.

Local long-term

Local long term DNELs for dermal exposure could not be determined, since no effects were observed. 

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information