The Contribution of cocoa additive to cigarette smoking addiction

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