Theophylline

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: basic data given; comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Test substance purity without specification.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Theophylline

EC Number:

200-385-7

EC Name:

Theophylline

Cas Number:

58-55-9

Molecular formula:

C7H8N4O2

IUPAC Name:

1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione

Details on test material:

- Name of test material (as cited in study report): Theophylline; 1,3 - Dimethylxanthine;
- Lot/batch No.: W 39918; 44182;
- Expiration date of the lot/batch: January 1984.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: KFM, Fuellinsdorf/Switzerland;
- Mean weight at study initiation: males: 137 g; females: 159 g.
- Fasting period before study: 16 hours ante applicationem
- Housing: 5 animals per cage;
- Diet: Altromin 1320, Altromin GmbH, Lage/Lippe (Germany), ad libitum;
- Water: tap water, ad libitum;

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C +/- 2°C
- Humidity (%): 55 % +/- 5 %
- Air changes (per hr): 15 - 18 times per hour
- Photoperiod (hrs dark / hrs light): 12h/12h

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% Traganth in distilled water

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg b.w.

Doses:

0; 100; 215; 261; 316; 464; 1000 mg/kg b.w.

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Weighing was performed only at the beginning of the study for dose calculation. Observation of clinical signs was performed during the first 5 min; after 15 and 30 min; after 1; 3; 6; 24 hours and once daily afterwards with the exception of weekends and on holidays.
- Necropsy of survivors performed: yes.

Statistics:

Probit Analysis according to FINNEY for calculation of LD50, including 95 % Confidence Interval based on the frequency of death within 24 hours. In the case of late death also within 7 and 14 days, respectively.

Results and discussion

Effect levels

Effect levels 1

Sex:

female

Dose descriptor:

LD50

Effect level:

272 mg/kg bw

95% CL:

194 - 385

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

273 mg/kg bw

95% CL:

193 - 389

Mortality:

No mortality was observed in the control and at 100 mg/kg b.w.; 3/20; 9/20; 14/20; 20/20 and 20/20 animals receiving 215; 261; 316; 464; and 1000 mg/kg b.w., respectively, died within 24 hours.

Clinical signs:

other: 0 mg/kg b.w.: No abnormalities detected. 100 mg/kg b.w.: No abnormalities detected. 215 mg/kg b.w.: Increased respiratory frequency and eyelid closure was observed in females, only. 261 and 316 mg/kg b.w.: Increased respiratory frequency and eyelid clo

Gross pathology:

464 mg/kg b.w.: In some animals anaemia was observed.
Between 316 and 1000 mg/kg b.w.: Several dead animals that exhibited nonspecific bleeding in the thymus.

Any other information on results incl. tables

Dose	Animals	Exitus
	N		hours			days
mg/kg	males	total	1 - 3	4 - 6	7 – 24	1 - 14
0	10	0	0	0	0	0
100	10	0	0	0	0	0
215	10	1	1	0	0	0
261	10	6	2	0	4	0
316	10	6	5	0	1	0
464	10	10	6	2	2	0
1000	10	10	10	0	0	0
	females
0	10	0	0	0	0	0
100	10	0	0	0	0	0
215	10	2	2	0	0	0
261	10	3	2	0	1	0
316	10	8	5	0	3	0
464	10	10	10	0	0	0
1000	10	10	10	0	0	0