(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

mice in the 300-ppm group had bilateral ovarian cysts after 91 days of exposure. Rats showed
no evidence of damage to reproductive organs. In the National Toxicology Program (1986),
benzene was evaluated for toxicity over 90 days and 2 years in F344 rats and B6C3F1 mice at
oral gavage doses of 0 and 25–600 mg/kg/day, 5 days/week for 90 days; and 0, 5, 100, and
200 mg/kg/day for male rats, or 0, 25, 50, and 100 mg/kg/day for female rats and all mice for 2
years. No effects were seen in reproductive organs in either species treated for 90 days or in
rats treated for 2 years. Ovarian lesions ranging from atrophy to neoplasia were observed in
mice treated for 2 years, although no dose response was established, with a higher incidence of
lesions occurring in the lowest dose (25 mg/kg/day).
Spano et al. (1989) examined effects on mouse germ cells (C57Bl/Cne x C3H/Cne F1 male
mice) using flow cytometry DNA content measurements on testicular monocellular suspensions,
following a single oral dose by gavage of 0, 1, 2, 4, 6, and 7 mL/kg (approx. 0, 878, 1756, 3512,
5268, and 6146 mg/kg) benzene. Treatment did not affect body or testes weights, but did alter
the ratio of testicular cell types at the higher doses, suggesting acute toxicity to differentiating
spermatogonia, with substantial to complete recovery by 70 days post-exposure. Mice exposed
to benzene in intraperitoneal (ip) doses of 0.1–1.0 mL/kg (88–878 mg/kg) daily for 5 days
exhibited statistically significant dose-related increases in sperm-head abnormalities at
0.4 mL/kg and higher, with peak effect at 0.6 mL/kg (Topham, 1980). Benzene also caused
dose-related increases in chromosome aberrations in sperm of mice following single oral doses
of 0.25, 0.5, or 1.0 mL/kg benzene (Ciranni et al., 1991)
The ability of benzene to affect female reproductive fertility appears limited. The Kuna et al.
study suggests 300 ppm to be a NOAEL when exposures are limited to 6 hours/day. Effects on
male fertility have been assessed only indirectly. Male rats appear to be relatively resistant to
adverse effects of benzene exposure on fertility, as measured by insemination of females and
effects on reproductive organs. Male mice appear to be more sensitive than male rats in terms
of effects on the testes, and CD-1 mice appear to be more sensitive than B6C3F1 mice,
although differences in exposure routes complicate this comparison. There are no studies
available where both parental animals have been exposed to benzene prior to mating.
6.2.3.2 Developmental Toxicity
Possible toxic effects of benzene during the embryonic and fetal periods are included under the
heading of developmental toxicity. Transplacental genotoxicity is discussed in Section 6.2.2.3
of the genotoxicity section. Data are available on developmental effects of benzene during
embryogenesis in rats, mice, and rabbits, by the inhalation and oral routes - see Table 6.3, from
EPA IRIS (U.S. EPA 1998b). Studies describing exposures during both the embryonic and fetal
period, with subsequent examination of the fetuses (as would be done under current testing
guidelines), are not available.
Inhalation
Kuna and Kapp (1981) exposed pregnant Sprague Dawley rats to benzene concentrations of 0,
10, 50, and 500 ppm (0, 32, 160, and 1600 mg/m 3 ), 7 hours/day on GD6–15, with maternal
sacrifice at GD20. Hematological evaluations performed on GD 5 and 20 included red blood
cells (RBC), white blood cells (WBC), and differential counts. There were no maternal deaths,
illness, or hematologic changes. During GD5–15, decreased maternal body weight gains were
observed in the 50- and 500-ppm exposed groups, and increased body-weight gains were
observed in the 10- and 500-ppm groups during GD15–20. No differences from controls were
observed in the number of implantation sites per number of corpora lutea; incidences of
Benzene VCCEP Submission
March 2006
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