Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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Appendix D: Benzene SIDS Dossier
hydroquinone were also present, but not dose–dependent.)
Although dose–dependent, amounts of the 3 major metabolites
formed at lower exposures (5–500 ng/kg bwt) was
proportionately less than at higher doses. The relative
amount of each metabolite remained approx. constant over the
treatment range and followed the order:
unidentified > phenyl sulphate > muconic acid > phenyl
glucuronide > hydroquinone sulphate.
Comment: The unknown peak present in urine in these low–dose
studies has not been reported by other investigators using
higher benzene treatment; attempts to establish its identity
were unsuccessful.
In liver, muconic acid, catechol and hydroquinone were
formed in a dose–dependent manner (phenol present but not
dose–dependent). In plasma and bone marrow, none of the
metabolites were found to be dose–dependent.
TOXICOKINETICS OF LOW–DOSE BENZENE METABOLISM
AUCs showed that hydroquinone (149 fmol) and muconic acid
(56 fmol) were the major metabolites present in mouse liver
over 48 hr following administration of 5 ug benzene /kg bwt
(i.p.), with comparatively minor amounts of catechol (2
fmol) and phenol (3 fmol).
A similar metabolite profile was present in bone marrow,
however AUCs were much lower and muconic acid predominated
(6, 16, 1 and 3 fmol for hydroquinone, muconic acid,
catechol and phenol, respectively).
Minor amounts of metabolites were present in plasma, with
marginally more hydroquinone present than for the other 3
metabolites (1.8, 0.6, 0.3, 0.3; order as previous).
Comment: The AUC data were highly variable; the authors
suggest biological variation and sampling artefacts may have
been responsible (– AMS methodology considered highly
reliable, low inter–sample variation).
RELATIONSHIP BETWEEN DOSE AND ADDUCT FORMATION IN MICE
Graphical results of log–transformed data show that protein
and DNA adduct levels in liver and bone marrow at 1 hr and
12 hr increased in a dose dependent manner following
administration of benzene at doses of 5 ng/kg to 500 mg/kg
(i.p.).
Levels of both adducts in liver (but not bone marrow)
appeared to plateau at doses >50 mg/kg bwt and tended to be
higher 1 hr post–dosing.
In bone marrow, adduct levels were equivalent at both time
points for protein and higher at 12 hr post–dosing for DNA.
Comment: In very general terms, low doses of benzene (ng–ug
range) appeared to yield 10^1 to 10^2 pg bound benzene
– 333/957 –