Caffeine

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study (NTP)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: NTP protocol

Principles of method if other than guideline:

NTP Protocol

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Caffeine

EC Number:

200-362-1

EC Name:

Caffeine

Cas Number:

58-08-2

Molecular formula:

C8H10N4O2

IUPAC Name:

1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione

Details on test material:

- Name of test material (as cited in study report): Caffeine
- Analytical purity: 99.9%

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

continuously in the drinking water

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
19.7, 41.8, 85.4, 151.0, 271.9 mg/kg/d (males); 23.1, 51.0, 104.2, 174.2, 287.0 mg/kg/d (females)
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
188, 375, 750, 1500, 3000 ppm
Basis:
nominal in water

No. of animals per sex per dose:

12 males and 12 females per group

Control animals:

yes, concurrent no treatment

Details on study design:

Post-exposure period: none

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 500 ppm

Sex:

male/female

Basis for effect level:

other: The daily dose was calculated to be 151.0 mg/kg for males and 174.2 mg/kg for females.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

The aim of this study was to determine the dose levels for a 2-year chronic bioassay. 
Groups of 12 rats/sex were given the test substance in the drinking water at concentrations of 0 (control), 188, 375, 750, 1500, and 3000 ppm. 
According to the authors, based on data of body weights and water consumption, the daily doses were calculated to be 0, 19.7, 41.8, 85.4, 151.0, and 271.9 mg/kg for males and 0, 23.1,
51.0, 104.2, 174.2, and 287.0 mg/kg for females. All animals were sacrificed at the end of the treatment period; body and organ weights were recorded. 
Clinical chemical examinations were performed on animals from the 188, 750, and 3000 ppm and control groups. 
Microscopic pathology was performed on all lesions appearing grossly and routinely in all major systems in the high dose and control groups.
The body weight gains of all treated groups were decreased. 
The effect was significant in the highest dose only (reduction of 26%, males, 20%,  females). 
Both food and water consumption was decreased by ca. 10% in this group in both sexes. 
However, water consumption was increased at 750  ppm (both sexes) and at 375 ppm (females). 
No significant clinical symptoms were recorded in any group.
Clinical chemistry indicated some significantly increased and/or decreased serum aspartate aminotransferase and alanine aminotransferase values and significantly decreased
serum amylase values in treated rats; however, no dose-related patterns were established.
There were no significant treatment-related gross lesions.
Microscopic examination revealed alterations (cell enlargement) of the  salivary gland which were most marked in the high dose group, diminishing  with decreasing dose.
The observed effect in salivary gland was dose dependent in rats and mice in the highest dose group only, the authors gave no description about adverse effect. 
These is a functional adaptive and reversible effect of  salivary glands to well known pharmacological effect of caffeine (sympathicomimetic). 
The morphological changes correlate to this function  are so fare not considered to be an adverse effect of the substance.
According to the authors, these results indicated that the maximum tolerated dose to be used for a 2-year chronic bioassay should be 2000 ppm; doses of 0, 500, 1000, and 2000
ppm were recommended for this study.