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Administrative data

Description of key information

ORAL 
In a 90-day subchronic toxicity study (NTP 1983) Caffeine (purity 99.9%) was administered to 12 Fischer 344 rats/sex/dose in water at dose levels of 0, 188, 375, 750, 1500, 3000 ppm (0, 19.7, 41.8, 85.4, 151.0, 271.9 mg/kg bw/d for males); 0, 23.1, 51.0, 104.2, 174.2, 287.0 mg/kg bw/d for females).
The LOAEL is 3000 ppm. The NOAEL is 1500 ppm.

In a 90-day subchronic toxicity study (NTP 1983) Caffeine (purity 99.9%) was administered to 12 B6C3F1 mice/sex/dose in water at dose levels of 0, 94, 188, 375, 750, 1500 ppm (0, 21.4, 43.6, 85.4, 130.5, 167.4 mg/kg/d for males; 0, 24.6, 46.6, 87.9, 134.4, 179.4 mg/kg/d for females).
The NOAEL is 1500 ppm (the highest dose administered).

DERMAL and INHALATION
No valid studies are available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
151 mg/kg bw/day

Additional information

ORAL

In a 90-day subchronic toxicity study (NTP, 1983) Caffeine (purity 99.9%) was administered to 12 Fischer 344 rats/sex/dose in water at dose levels of 0, 188, 375, 750, 1500, 3000 ppm (0, 19.7, 41.8, 85.4, 151.0, 271.9 mg/kg bw/d for males; 0, 23.1, 51.0, 104.2, 174.2, 287.0 mg/kg bw/d for females). Doses had been selected based on the results of a 14 -day study.

The body weight gains of all treated groups were decreased. The effect was significant in the highest dose group 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 far not considered to be an adverse effect of the chemical.

  • The LOAEL is 3000 ppm. The NOAEL is 1500 ppm.

This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in rats.

In a subchronic toxicity study (NTP, 1983) Caffeine (purity 99.9%) was administered to 12 B6C3F1 mice/sex/dose in water at dose levels of 0, 94, 188, 375, 750, 1500 ppm (0, 21.4, 43.6, 85.4, 130.5, 167.4 mg/kg/d for males; 0, 24.6, 46.6, 87.9, 134.4, 179.4 mg/kg/d for females).

Mean body weights were significantly depressed (by >10%) in males treated with 188, 375, and 750 ppm. Final mean body weights were significantly decreased at 94, 188, 375 ppm (both sexes), and at 750 ppm (males only). Food consumption was unaffected. Water consumption was decreased by 10% and more in the groups given 1500 and 750 ppm (both sexes) and increased by 10% and more in all other treated group (both sexes). No significant clinical symptoms were recorded in any group. Clinical chemistry indicated significant decreases in the levels of serum amylase (1500 ppm, both sexes), serum aspartate aminotransferase (375 ppm, females), and alanine aminotransferase (1500 ppm, females). However, no dose-related trends were indicated. There were no significant treatment-related gross or microscopic lesions, though microscopic examination revealed some alterations of the salivary gland at the upper limits of normal in the high dose group.

  • The NOAEL is 1500 ppm (the highest dose administered).

This subchronic toxicity study in the mouse is acceptable and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in mice.

DERMAL and INHALATION

No valid studies are available.

HUMAN DATA:

Cardiovascular disease

No association between increased caffeine consumption and increased mortality due to cardiovascular disease was found(Martin et al., 1988).

Earlier studies suggested an association of caffeine consumption of more than 6 cups of coffee with coronary heart disease (CHD)(Paul et al., 1963, Boston Collaborative Drug Surveillance Program, 1972, Jick et al., 1973). In more recent years, retrospective(Hennekens et al., 1976, Rosenberg et al., 1980, Willett et al., 1996)and prospective studies have consistently failed to demonstrate an association between caffeine and CHD(Yano et al., 1977, Heyden et al., 1978, Murray et al., 1981, Welin et al., 1984, Grobbee et al., 1990, Rosengren and Wilhelmsen, 1991, Hart et al., 1997). In a case-control study neither caffeinated nor decaffeinated coffee (drinking³4 cups/day of caffeinated coffee compared to drinking£1 cup/week, resp.³1 cup/day of decaffeinated coffee compared to nondrinkers) was associated with the risk of myocardial infarction(Sesso et al., 1999).

 

Hypertension

Short-term clinical studies have shown that in caffeine-naive subjects, 250 mg of caffeine increased systolic blood pressure(Robertson et al., 1978, Ammon et al., 1983).In a cross-sectional study of 30,000 middle aged men consuming caffeine showed an inverse association with systolic and diastolic blood pressure(Stensvold et al., 1989). Similar findings were reported in a multiple risk factor intervention trial(Stamler et al., 1997)and in a cross-sectional study(Periti et al., 1987). Surveys of the general population demonstrated a positive correlation between caffeine consumption and systolic but not diastolic blood pressure(Lang, et al. 1983a, Lang et al., 1983b). No relationship between increasing caffeine consumption and elevations of blood pressure was seen in large cross-sectional study in employees(Bertrand et al., 1978).An immediatedose-related difference in systolic and diastolic blood pressure were seen in healthy nonsmokers(Lane et al., 1998)and in hypertensive patients(Rachima-Maoz et al., 1998).

Though consumption of caffeine (eight cups of regular coffee corresponding to 500 mg caffeine per day) may exhibit acute increases in blood pressure, the long-term effects appear to be minimal. After one to four days of regular consumption a tolerance develops, with blood pressure returning to previous levels.

 

Arrhythmias

Heavy coffee consumption (³9 cups/day) was associated with more than twice the likelihood of ventricular premature beats in a population survey(Prineas et al., 1980).However,Sutherland et al., 1985, Roberston et al., 1981, Myers et al., 1987, Newsby, 1996reported that caffeine doses up to 500 mg/day do not affect cardiac rhythm in normal subjects and patients.

 

Lipids, glucose

Experimental studies does not reflect a caffeine effect on blood cholesterol. Changes in blood cholesterol are similar in individuals consuming decaffeinated coffee or regular coffee(van Dusseldrop et al., 1990, Superko et al., 1991). Blood cholesterol levels were also comparable in subjects given placebo or 600 mg caffeine(Herbert et al., 1987). A meta-analysis of randomized controlled clinical trials showed increased serum lipids in studies of patients with hyperlipidemia and in trials of caffeinated or boiled coffee. Trials using filtered coffee demonstrated very little increase in serum cholesterol. Consumption of unfiltered, but not filtered, coffee increases serum levels of total and LDL cholesterol (Jee et al., 2001). An insulin independent rise in blood glucose was seen in subjects receiving 200 mg caffeine(Pizziol et al., 1998).

 

Calcium metabolism

Increased urinary and fecal excretion of calcium and other minerals associated with dietary caffeine have been reported(Massey and Wise, 1984, Massey and Opryszek, 1990, Whiting, 1990).Although caffeine caused a small positive increase in urinary calcium excretion, it did not affect overall bone density(Lloyd et al., 1991).Negative findings with respect to caffeine intake, bone mineral content, and risk of fractures were reported(Johansson et al., 1992, Harris and Dawson-Hughes, 1994, Kreiger et al., 1992, Lloyd, 1997). Other reports suggested that consumption of more than 2 cups of coffee a day may be associated with an increased risk of hip fracture(Kiel et al., 1990, Hernandez-Avila et al., 1991). However moderate caffeine intake (100 mg/day) appears not be associated with significant reduction in bone gain(Packard and Recker, 1996, Lloyd et al., 1998).

 

Fibrocystic breast disease

There is little evidence to support an association between caffeine intake (up to 6 cups of coffee and more per day) and an increase in the incidence of benign breast disease or an affection of its course when this condition is present (Levinson and Dunn, 1986, Lawson et al., 1981, Marshall et al., Heyden and Fodor, 1986, Lubin et al., 1985, Rohan et al., 1989).

 

Tolerance and withdrawal

Case reports and clinical studies of caffeine withdrawal most frequently reported symptoms of abrupt withdrawal as mild to moderate headache beginning 12-24 hours after terminating intake (300 mg/day) and lasting up to a week(Griffiths and Mumford, 1995, Griffiths and Woodson, 1988, Evans and Griffiths, 1992). Decreased responsiveness to daily caffeine (500 mg/day) administration with respect to blood pressure(Ammon et al., 1983, Roberston et al., 1981), diuresis (minimal effectiv diuretic dose 70 mg/day)(Eddy and Downs, 1928), and plasma epinephrine, norepinephrine, and plasma renin activity (250 mg/day)(Robertson et al., 1978),but not to the effect of caffeine on urinary calcium excretion (300 mg/day) was reported(Massey and Opryszek, 1990).No effect on mood and alertness was seen after single caffeine dose (600 mg/day)(Sicard et al., 1996)orwithdrawal(300 mg/day)(Comer et al., 1997).Other studies on caffeine deprivation found an association with decreased vigor and performance on reaction andincreased fatigue (250 mg/day)(Phillips-Bute and Lane, 1998, Bernstein et al., 1998).

Justification for classification or non-classification

Based on the data available for Caffeine, there is no need for classification.