The Contribution of cocoa additive to cigarette smoking addiction
The Contribution of cocoa additive to cigarette smoking addiction The Contribution of cocoa additive to cigarette smoking addiction
Page 16 of 207 RIVM report 650270002 Theobromine and gastrointestinal tract effects (1). It has been stated that ‘in large doses’ theobromine may cause nausea and anorexia. In a study of 13 volunteers who consumed 200 mg theobromine orally three times during a 24 h period, no clinical symptom or other pharmacological activity was observed. Ingestion of theobromine in sweet chocolate at a dose of 6 mg/kg bw per day had no effect on clinical parameters in 12 human subjects (4). Animal Oral: LD50 rat = 950 mg/kg bw (for the sodium acetate) (4) LD50 rat = 1265 mg/kg (1) LD50 mice = 1356 mg/kg bw (for the sodium acetate) (4) LD50 mice = 837 mg/kg (1) LD50 dog = 300 mg/kg bw. (1, 4) Local tolerance Human No data available. Animal High doses – 250 – 300 mg/kg bw (mature animals) and 500 mg/kg bw (immature animals) – have been shown to cause complete thymic athrophy in male and female rats. This effect was seen in hamsters only at a level of 850 mg/kg bw and in mice at levels of 1840 – 1880 mg/kg bw (4). Repeated dose toxicity Subacute In a study where male dogs were fed 100 – 150 mg theobromine per kg bw for 21 – 28 days, a degenerative and fibriotic lesion in the right atrial appendage of the heart was reported. (4) Semichronic Theobromine fed to male and female Sprague-Dawley rats at levels of 0, 0.02, 0.1 and 0.2 % of a chow diet for 90 days (corresponding to 25, 125 and 250 mg/kg bw/day), revealed only a reduction in body weight gain and testicular weight in males at the high dose. There were no pathological lesions and no haematological changes observed (4). Chronic Daily intake by humans of 50 – 100 g cocoa (0.8 – 1.5 g theobromine) has been associated with sweating, trembling and severe headache (4). Carcinogenicity Human There is inadequate evidence for the carcinogenicity of theobromine in humans (4). It has been suggested that older men (>67) consuming 11 to 20 and over 20 mg of theobromine per day are at increased risk of prostate cancer (odds ratio (OR) for all tumors = 2.06 and 1.47, respectively; OR for aggressive tumors (defined as undifferentiated localized tumors and well-differentiated to undifferentiated regional or distant tumors) = 1.90 and 1.74, respectively) (24). It should be noted that these data are based on a small number of cases (
RIVM report 650270002 Page 17 of 207 Theobromine is not representative for the common population. Animal No data on the carcinogenicity of theobromine were available (4). Reproduction toxicology Human No data were available to evaluate the carcinogenicity of theobromine per se (4). Animal Oral administration of high doses (90 – 600 mg/kg bw per day) theobromine to rats for 28 days or 64 weeks caused severe testicular atrophy, which was largely irreversible. Administration of lower levels for prolonged periods had no significant adverse effect on the testis. In mice, (doses 300 – 1850 mg/kg bw per day) testicular changes were seen only at concentrations that caused considerable mortality (4). No adverse reproductive effect was observed in a three generation study in rats given cocoa powder containing 2.50 – 2.58 % theobromine in their diet at concentrations of 0, 1.5, 3.5 and 5.0 % (4). Theobromine is used as an experimental teratogen. Intraperitoneal-Mouse TDLo (LOAEL): 500 mg/kg (female 13d post): teratogenic effects (1). Teratogenic effects (decreased fetal body weight at doses of 125 or 200 mg/kg bw, and increased skeletal variations at 75 mg/kg and over) were observed in rabbits after gavage but not after dietary administration of theobromine. No teratogenic effect was seen in rats (4). Sertoli cells are the target cells of theobromine toxicity on rat testes and reproductive toxicity (25). Theobromine caused vacuolation within the Sertoli cell, abnormally shaped spermatids, and failed release of late spermatids in treated rats. The ability of theobromine to alter testis structure after oral exposure has been demonstrated (26). Mutagenicity Human According to the IARC concensus report of 1991 no data were available (4). According to the SAX Dangerous properties and environmental fate Handbook of 1999 human mutation data are reported (1). Animal Mutation in Microorganisms-Euglena gracilis 600 mg/L (1). Sister Chromatid Exchange-Human:lymphocyte 100 mg/L (1). In vivo, theobromine did not induce dominant lethal effects in mice or rats. It induced sister chromatid exchange and micronuclei but not chromosomal aberrations in the bone marrow of Chinese hamsters. In human cells in vitro, theobromine induced sister chromatid exchange and chromosomal breaks. In cultured mammalian cells, it induced gene mutations and sister chromatid exchange but not chromosomal aberrations or cell transformation. In plants, theobromine did not induce chromosomal aberrations. It induced gene mutations in lower eukaryotes and bacteria but gave negative results in the Salmonella/mammalian microsome assay (4). Other
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Page 16 <strong>of</strong> 207 RIVM report 650270002<br />
<strong>The</strong>obromine<br />
and gastrointestinal tract effects (1).<br />
It has been stated that ‘in large doses’ theobromine may cause nausea and anorexia.<br />
In a study <strong>of</strong> 13 volunteers who consumed 200 mg theobromine orally three times<br />
during a 24 h period, no clinical symp<strong>to</strong>m or other pharmacological activity was<br />
observed. Ingestion <strong>of</strong> theobromine in sweet chocolate at a dose <strong>of</strong> 6 mg/kg bw per<br />
day had no effect on clinical parameters in 12 human subjects (4).<br />
Animal<br />
Oral: LD50 rat = 950 mg/kg bw (for the sodium acetate) (4)<br />
LD50 rat = 1265 mg/kg (1)<br />
LD50 mice = 1356 mg/kg bw (for the sodium acetate) (4)<br />
LD50 mice = 837 mg/kg (1)<br />
LD50 dog = 300 mg/kg bw. (1, 4)<br />
Local <strong>to</strong>lerance<br />
Human<br />
No data available.<br />
Animal<br />
High doses – 250 – 300 mg/kg bw (mature animals) and 500 mg/kg bw (immature<br />
animals) – have been shown <strong>to</strong> cause complete thymic athrophy in male and female<br />
rats. This effect was seen in hamsters only at a level <strong>of</strong> 850 mg/kg bw and in mice at<br />
levels <strong>of</strong> 1840 – 1880 mg/kg bw (4).<br />
Repeated dose <strong>to</strong>xicity<br />
Subacute<br />
In a study where male dogs were fed 100 – 150 mg theobromine per kg bw for 21 –<br />
28 days, a degenerative and fibriotic lesion in the right atrial appendage <strong>of</strong> the heart<br />
was reported. (4)<br />
Semichronic<br />
<strong>The</strong>obromine fed <strong>to</strong> male and female Sprague-Dawley rats at levels <strong>of</strong> 0, 0.02, 0.1<br />
and 0.2 % <strong>of</strong> a chow diet for 90 days (corresponding <strong>to</strong> 25, 125 and 250 mg/kg<br />
bw/day), revealed only a reduction in body weight gain and testicular weight in males<br />
at the high dose. <strong>The</strong>re were no pathological lesions and no haema<strong>to</strong>logical changes<br />
observed (4).<br />
Chronic<br />
Daily intake by humans <strong>of</strong> 50 – 100 g <strong>cocoa</strong> (0.8 – 1.5 g theobromine) has been<br />
associated with sweating, trembling and severe headache (4).<br />
Carcinogenicity<br />
Human<br />
<strong>The</strong>re is inadequate evidence for the carcinogenicity <strong>of</strong> theobromine in humans (4).<br />
It has been suggested that older men (>67) consuming 11 <strong>to</strong> 20 and over 20 mg <strong>of</strong><br />
theobromine per day are at increased risk <strong>of</strong> prostate cancer (odds ratio (OR) for all<br />
tumors = 2.06 and 1.47, respectively; OR for aggressive tumors (defined as<br />
undifferentiated localized tumors and well-differentiated <strong>to</strong> undifferentiated regional<br />
or distant tumors) = 1.90 and 1.74, respectively) (24). It should be noted that these<br />
data are based on a small number <strong>of</strong> cases (
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