Safety evaluation of certain food additives - ipcs inchem

524 FURAN-SUBSTITUTED ALIPHATIC HYDROCARBONS
and human peripheral lymphocytes, study results were inconsistent, with both
negative (2,5-dimethylfuran, O-ethyl-S-(2-furylmethyl)thiocarbonate) and positive
(2-methylfuran, 2,5-dimethylfuran) results reported. Although positive results were
reported in the chromosomal aberration assay in CHO cells with 2-methylfuran and
2,5-dimethylfuran, relatively high concentrations were utilized (i.e. up to 13 220 and
1923 μg/ml, respectively); the statistical significance of the results was not specified,
and the potential cytotoxicity was not monitored in the assay. Moreover, as
previously discussed, positive in vitro results of chromosomal aberrations are
difficult to interpret in the presence of concomitant cytotoxicity and cell cycle delay,
which, based on the results of the studies, are a feature of the furan derivatives.
Therefore, it may be expected that mammalian cells in culture might not have
adequate metabolic capacities to counter this toxicity. In fact, with the exception of
one assay in which clastogenic activity was reported for a single compound (i.e. 2furyl
methyl ketone) with a metabolic activation system, results obtained with other
representative furan derivatives demonstrated a reduction in the frequency of
chromosomal aberrations in the presence of metabolic activation. Furthermore,
unlike the positive results reported for 2,5-dimethylfuran among several other
compounds evaluated in CHO cells at the high concentrations used in the study of
Stich et al. (1981), 2,5-dimethylfuran, tested at lower concentrations in V79 cells,
did not exhibit clastogenic activity (Ochi & Ohsawa, 1985). The negative findings in
the human hepatocyte DNA damage assay provide evidence that the chromosomal
aberration findings are not due to a DNA-reactive mechanism.
Three representative compounds were studied in in vivo assays. With
2-methylfuran, no increase in chromosomal aberrations was found in either
mouse bone marrow cells or spermatocytes. In a study in which mild clastogenic
activity was reported in mouse bone marrow cells at the middle and high doses
of 2-furyl methyl ketone (i.e. 40 and 60 mg/kg bw, respectively), at which the
authors also reported significant mitodepression following single- and multipledose
administrations, no increase in chromosomal aberrations was observed in the
spermatocytes obtained from the same mice, and the weak clastogenic effects
achieved statistical significance only after repeated daily exposure to near-lethal
doses. A study from the same laboratory reported induction of SCEs in mouse bone
marrow cells by 2-furyl methyl ketone. However, 2-furyl methyl ketone did not elicit
UDS in hepatocytes isolated from rat liver, suggesting that any possible in vivo
genotoxicity is not attributable to DNA reactivity. The frequency of micronucleus
formation in bone marrow cells of mice administered single doses of O-ethyl-S-(2furylmethyl)thiocarbonate
was comparable with control values (Verspeek-Rip,
2001), although adequacy of exposure was not demonstrated.
In conclusion, results of the in vitro genotoxicity/mutagenicity tests revealed
mixed results, with positive results reported less frequently in the presence of an
activation system. This could indicate metabolic detoxication of these substances.
The in vivo single-dose studies with 2-furyl methyl ketone did not indicate evidence
for genotoxicity, whereas two repeat-dose studies showed weak effects for
induction of chromosomal aberrations and SCEs. However, evidence indicates that
2-furyl methyl ketone does not exhibit DNA reactivity. The basis for the positive
clastogenicity findings remains unclear.