Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
No data
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, reasonably well-documented publication which meets basic scientific principles. Study carried out with caffeine, a key component of cocoa.

Data source

Reference Type:

Materials and methods

Test guideline
no guideline available
not specified
Principles of method if other than guideline:
The pharmacokinetics of inhaled caffeine were assessed in ten “chronic, treatment-resistant heroin users”. The trial was performed in accordance with Dutch Law, ICH and EU Guidelines for Good Clinical Practice and the protocol reviewed by the Central Committee on Medical Ethics of the Netherlands (KEMO).

GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Constituent 2
Reference substance name:
1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-
EC Number:
1H-Purine-2,6-dione, 3,7-dihydro-1,3,7-trimethyl-
Details on test material:
- Name of test material (as cited in study report): Caffeine
- Molecular formula (if other than submission substance): C8H10N4O2
- Molecular weight (if other than submission substance): 194.19 g/mol
- Smiles notation (if other than submission substance): c12c(n(c(=O)n(c1=O)C)C)ncn2C
- InChl (if other than submission substance): 1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3
- Structural formula attached as image file (if other than submission substance): see Fig. 2
- Substance type:
- Physical state: solid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data

Test animals

other: Not applicable
not specified

Administration / exposure

Route of administration:
not specified
Details on exposure:
On five consecutive days, a group of ten volunteers (heroin users undergoing methodone treatment) were each supplied with one tablet containing 100 mg caffeine and diacetylmorphine base (25, 50 or 100 mg). The tablet was then heated, either on aluminium foil with a lighter or on a heating plate and the subject attempted to inhale the fumes and the resultant vapour inhaled. The duration of inhalation was 10 minutes on average (ranging from 7-14 minutes).

Throughout the study volunteers were allowed their prescribed medication (methodone) and unrecorded access to coffee and cocoa products.
Duration and frequency of treatment / exposure:
10 minutes, daily for 5 days.
Doses / concentrations
Doses / Concentrations:
The tablet contained 100 mg caffeine in combination with 25, 50 or 100 mg diacetylmorphine. The estimated inhaled caffeine dose was 60 mg (see results).

No. of animals per sex per dose / concentration:
Ten volunteers, sex unspecified

Control animals:
other: Not applicable
Details on study design:
Volunteers selected their preferred inhalation method; either heating the tablet on a piece of aluminium foil with a lighter or on a heating plate.

On each of the five consecutive days, 14 blood samples were taken: 1 prior to inhalation of the caffeine/diacetylmorphine formulation and at specified intervals 1 to 480 minutes after inhalation exposure.

Plasma concentrations of caffeine and its dimethylxanthine metabolites (theobromine, paraxanthine and theophylline) were measured and caffeine and theobromine levels adjusted to take account of presumed typical coffee and cocoa product ingestion.

Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): blood, plasma
- Time and frequency of sampling: 1 min before and 1, 2, 5, 7.5, 10, 15, 22.5, 30, 45, 60, 120, 240 and 480 min after exposure

2545 plasma samples available for analysis

- Tissues and body fluids sampled (delete / add / specify): plasma- Time and frequency of sampling: 1 min before and 1, 2, 5, 7.5, 10, 15, 22.5, 30, 45, 60, 120, 240 and 480 min after exposure
- From how many animals: (samples pooled or not):No data
- Method type(s) for identification: HPLC - Limits of detection and quantification: 200 ng/ml for caffeine and 50 ng/ml for theobromine, paraxanthine and theophylline
- Other: Accuracy 90-110% and precision were <10 %

No data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Caffeine was “very rapidly” absorbed from the lungs.
Details on excretion:
Caffeine elimination rate was estimated to be 0.15 hr-1

The availability of caffeine from this inhalation exposure (i.e. the percentage inhaled) was estimated to be approximately 60%. The absorption of inhaled caffeine was approximately 100%

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Paraxanthine, theophylline and theobromine

Applicant's summary and conclusion

Interpretation of results (migrated information): other: Caffeine “very rapidly” absorbed from the lungs, with the absorption of inhaled caffeine estimated to be approximately 100%. Caffeine concentrations in the blood peaked within a few minutes and slowly declined over the following 8 hours.
When volunteers were exposed for about 10 minutes to fumes generated from a tablet containing 100 mg caffeine and diacetylmorphine (25, 50 or 100 mg), about 100% of the inhaled caffeine was absorbed into the blood.
Executive summary:

Volunteers (who had previously inhaled heroin on a regular basis) were exposed for about 10 minutes/day on five consecutive days to the fumes generated on heating a tablet containing 100 mg caffeine and up to 100 mg diacetylmorphine (a heroine substitute), Blood samples were taken and the concentrations of caffeine and its metabolites measured. Caffeine plasma concentrations were best described by a two compartmental model and its metabolites by single compartment models. Caffeine elimination rate was estimated to be 0.15/hourand absorption of the inhaled amount (which accounted for 60% of the tablet caffeine) was estimated to be approximately 100% after inhalation.