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In a carcinogenicity study (Mohr et al., 1984), food grade Caffeine (purity not further stated) was administered to male and female Sprague-Dawley rats in water at dose levels of 0, 200, 430, 930, or 2000 ppm for 104 weeks. 
A NOAEL / LOAEL was not established.
At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. Exposure to caffeine for 2 years did not enhance or induce neoplasia in the Sprague-Dawley rats.

Key value for chemical safety assessment

Additional information

In a carcinogenicity study (Mohr et al., 1984), food grade Caffeine (purity not further stated) was administered to male and female Sprague-Dawley rats in water at dose levels of 0, 200, 430, 930, or 2000 ppm (0, 12, 26, 49, 102 mg/kg bw/d for males; 0, 15, 37, 80, 170 mg/kg bw/d for females) for 104 weeks, with interim sacrifices being conducted after 3, 6, and 12 months of treatment. 50 rats/sex/dose were used for the dosed groups; 100 rats/sex were used for the control group.

There were no compound related effects in mortality, clinical signs, hematology, clinical chemistry, or gross and histologic pathology. Body-weight gain was considerably depressed by high caffeine intake (especially at 930 and 2000 mg/litre). Terminal body weights of treated animals were lower than terminal control weights by 25% at the highest dose and by approximately 11% at the next lower level. There was no difference between the sexes in this respect. Although food consumption was somewhat lower at the highest caffeine dose, there was no effect on the efficiency of food utilization. No data are reported on organ weights.

A NOAEL / LOAEL was not established.

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. No unusual tumours or sites of origin for neoplastic growth were found in any animal receiving caffeine. Neoplasms found in various organs showed incidences not exceeding those seen in controls. Thus, exposure to caffeine for 2 years did not enhance or induce neoplasia in the Sprague-Dawley rats.

This carcinogenicity study in the rat is acceptable and does satisfy the guideline requirement for a carcinogenicity study (OECD 451) in rats.

HUMAN DATA:

Heavy coffee consumption tends to be associated with other risk factors for various types of cancer, e.g. smoking, alcohol, physical inactivity (Giovannucci, 1998). Residual confounding might explain weak positive associations between caffeine consumption and lung, bladder, or pancreas cancer.

Based on the currently available literatureNehlig and Debry’s(1996)conclusion that in the doses usually consumed by man, coffee does not have any potential carcinogenic effect can still be supported.

Whether the consumption of doses higher than 4 mg/kg/day slightly enhances or lowers the risk for some cancer types is currently not clear.

The IARC evaluates the carcinogenicity in humans of caffeine as inadequate evidence (IARC 1991).

 

Different sites

The effect of caffeine consumption (av. 317 mg/day) on mortality was evaluated in a historical cohort study of 10,064 diagnosed hypertensive individuals participating in the Hypertension Detection and Follow-up Program from 1973 to 1979. No evidence was found for an association between increased level of caffeine consumption (up to > 428 mg/day) and increased cancer mortality during the following four years(Martin et al., 1988).

 Breast

Several case-control studies provided no association between coffee intake (up to³7 cups/day) and breast cancer risk(IARC, 1991).Also new case-control studies confirmed this result(Hunter, 1992, McLaughlin et al., 1992, Folsom et al., 1993, Levi et al., 1993, Smith et al., 1994, Tavani et al., 1998).

 Colon

Cohort studies that addressed the issue of coffee drinking (up to³3 cups/day) and risk of cancer of the colon have generally been interpreted as showing no association. There are case-control studies that indicated inverse associations and others find a risk. Bias and confounding could not be excluded as the source of the apparent associations(IARC, 1991). In recent case-control and cohort studies no increased risk of colorectal cancer from caffeine intake (up to³7 cups/day) was found(Cipriani and Geddes, 1996, Giovannucci, 1998, Hartman et al., 1998, Tavani et al., 1997).The lower risk of colorectal cancer with high vs. low coffee consumption as determined in the meta-analysis byGiovannucci (1998)might be due to an avoidance of coffee by unidentified high-risk individuals, or due to enhanced colonic motility induced by coffee, or due to antimutagenic components in coffee (not necessarily caffeine).

 Bladder

In cohort studies on coffee consumption neither an increase nor a decrease risk for bladder cancer was found. Several case-control studies showed a weak positive association, while others did not. Taken as a whole, the data are consistent with a weak positive relationship between coffee consumption (up to >5 cups/day) and the occurrence of bladder cancer, but the possibility that this is due to bias or confounding cannot be excluded(IARC, 1991).

 Non-Hodgkin lymphoma, lung, pancreas

Cohort studies on the relationship between coffee consumption and pancreatic cancer did not report a significant association with increased consumption; any nonsignificant increase was reduced after adjustment for smoking. In an early case-control study a positive relationship between coffee consumption (up to³5 cups/day) and pancreatic cancer was reported. Several subsequent reports (coffee intake³7 cups/day) have been less positive overall. Potential biases associated with the comparability of case and control groups also complicate interpretation, and methodological problems were noted in some studies(IARC, 1991). A recent case-control study showed a U-shaped dose-response relationship between coffee intake (never, occasionally, and 3+ cups/day) and the relative risk for pancreatic cancer, suggesting a preventive effect of small amounts of coffee. However, the authors did no present data to verify this suggestion (Nishi et al., 1996).

In a case-control study no association between coffee consumption (up to 4 cups/day , resp. 2 or more cups/day) and non-Hodgkin´s lymphoma was found (Tavani et al., 1994). Concerning lung cancer, there have been reports of studies showing no or weak associations with the consumption of caffeine-containing drinks (Mendilaharsu et al., 1998, and others quoted byMendilaharsu et al., 1998,Jacobsen et al., 1986).Data are inadequate for an assessment

Justification for classification or non-classification

There is no need to classify Caffeine for carcinogenicity according to the Directive 67/548/EC or GHS criteria.