Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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Flag: Risk Assessment
01–JUL–2005 (424)
Species: rat Sex: male/female
Strain: Sprague–Dawley
Route of administration: inhalation
Exposure period: 15 weeks
Frequency of treatment: 4 hours per day/5 days per week/7 weeks and then 7
hours per day/5 days per week/8 weeks
Post exposure period: until spontaneous death
Doses: 200 ppm (converts to 0.65 mg/l); 70 males and 59
females
Control Group: yes, concurrent vehicle
Method: other
GLP: no data
Test substance: other TS
Remark: Control group consisted of 158 male and 149 female rats
exposed in utero (as 12–day–old embryos) and postnatally to
air for a total of 104 weeks. Twelve–day–old embryos were
exposed in utero and postnatally to 0.65 mg/l, 4 hours/day,
5 days/week for 7 weeks and then for 7 hours/day, 5
days/week for 8 weeks. The animals were weighed every 2
weeks during the treatment period and every 8 weeks during
the postexposure observation period. Complete autopsy was
performed on each animal and histological examination made
of the major organs. The rats may also have had some oral
exposure through their mothers’ milk at weaning.
Benzene concentration analysed by GC.
Significant methodological deficiencies
no data about analytical concentration, one concentration
tested, controls not sham–exposed for the same period, low
number of animals (minimal 21/sex in treatment or 11/sex in
control group) for final determination of specific tumor
incidence, no statistical evaluation, limited histopathology.
The US Environmental Protection Agency (EPA) Gene–Tox
Carcinogenesis Panel (Nesnow et al. 1986) reevaluated the raw
data from these studies including the slides used for
histopathology determinations. Their comment on this Maltoni
study was that it was inconclusive (without giving any
detailed reasoning).
To the German Rapporteur, their decision seems to be
explainable since the study design, data evaluation and
documentation were not compliant to standard carciongenicity
bioassays. The target organs showed consistency to those of
other studies, therefore the rapporteur interpreted the data
from the Maltoni studies to give supportive evidence on
benzene carcinogenicity via the inhalation route.
Result: No effects were seen on survival rate or body weight. When
the sexes were considered both individually and combined,
increases were seen in the incidences of Zymbal gland
carcinomas (combined incidence = 3.9 compared with 0.7% in
the control group), oral cavity carcinomas (incidence = 19
compared with 0%), nasal cavity carcinomas (incidence = 15
Appendix D: Benzene SIDS Dossier
– 532/957 –