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Toxicological information

Repeated dose toxicity: oral

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Administrative data

sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: guideline study (NTP)

Data source

Reference Type:
study report

Materials and methods

Test guideline
according to guideline
other: NTP protocol
Principles of method if other than guideline:
NTP Protocol
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Name of test material (as cited in study report): Caffeine
- Analytical purity: 99.9%

Test animals

Fischer 344

Administration / exposure

Route of administration:
oral: drinking water
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 / concentrationsopen allclose all
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)
actual ingested
Doses / Concentrations:
188, 375, 750, 1500, 3000 ppm
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:
Effect level:
1 500 ppm
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.

Applicant's summary and conclusion

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