(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

esorbed, dead, or live fetuses; or fetal sex distribution. Fetal crown-rump length was
decreased in the 500ppm group, and the mean body weights of live fetuses were decreased in
the 50 and 500ppm groups. Abnormalities were observed in four litters exposed to 500 ppm:
one fetus with exencephaly, one fetus with angulated ribs, and two fetuses in two separate
litters with ossification of forefeet out of sequence. Other skeletal variations included delayed
ossification of skull, vertebral column, ribcage, pelvic girdle, and extremities, and fewer tailbones
than controls. Statistical analyses of skeletal variants and abnormalities were based on
the fetus rather than the litter. The maternal and developmental LOAEL was 50ppm
(160mg/m 3 ), and the NOAEL was 10ppm (32mg/m 3 ). Developmental effects were observed at
concentrations that caused maternal toxicity.
As discussed in the Reproductive Toxicity section, a separate study by Kuna (1992) evaluated
some developmental parameters of offspring of female Sprague Dawley rats exposed at vapor
concentrations of 0, 1, 30, and 300ppm (0, 3.2, 96, and 960mg/m 3 ), 6 hours/day, 5 days/week
for 10 weeks premating and mating, then daily on GDs 0–20 and lactation days 5–20. No
treatment-related effects were observed on maternal mortality, estrus cycle, body weight and
body-weight changes, physical parameters, pregnancy rate and length of gestation, and number
of live and dead pups at birth and sex distribution. No effects were observed on pup survival.
Reduced body weight and absolute organ weight trends were observed in 21-day-old pups from
the 30 and 300ppm groups, but the only statistically significant result was reduced liver weight in
the female pups of 300ppm dams. Therefore, the developmental toxicity NOAEL from this study
appears to be 300 ppm for male pups and 30 ppm for female pups. While the Kuna (1992)
study is somewhat limited in developmental parameters (e.g., no skeletal growth parameters
were reported), an important aspect of the study is that it exposed the developing rats
throughout gestation and through lactation (days 5–20), which is an important period of
development for newborn rats. Kuna (1992) reported no effect on newborn pup weight,
suggesting that there would not be additional growth decrements due to exposure during the
fetal period up to 300 ppm.
In a study by Coate et al. (1984), inhalation doses of 0, 1, 10, 40, and 100 ppm were
administered to Sprague Dawley rats during GDs 6–15,. No adverse effects were reported in
maternal body-weight gain, resorption rate, or ability to deliver offspring. Fetuses in the 100ppm
group exhibited significant decreases (p≤0.05) in fetal body weight, and statistically nonsignificant
decreases in fetal length. Delays in ossification of skull, vertebral centra, and
extremities occurred at 100 ppm. The investigators concluded that benzene was weakly toxic to
the fetus at 100 ppm, a concentration that was not toxic to the dam. The developmental LOAEL
was 100ppm, and the NOAEL was 40 ppm. A prior study conducted for the American
Petroleum Institute (API, 1982), reported statistically significant increases in resorptions at both
doses of 10 and 40 ppm, with no other maternal or fetal effects. However, control rats appeared
to have an abnormally low resorption incidence, making the apparent LOAEL of 10ppm
questionable, especially considering subsequent results by Coate et al. (1984). Green et al.
(1978) reported that benzene concentrations of 100, 300, and 2200 ppm on GDs 6–15, with
sacrifice on GD 21, were maternally toxic to rat dams at 2200 ppm (body weight reduced from
GD8-20). These concentrations did not induce malformations but did induce fetal toxicity,
manifested as skeletal variants in all dose groups at concentrations that were not maternally
toxic. In the 2200-ppm group, the number of females with unossified sternebrae was
significantly increased over males, suggesting increased sensitivity to benzene-induced effects.
Investigators who exposed rats to benzene for 24 hours/day reported increased toxicity for
similar endpoints. Hudak and Ungváry (1978) administered benzene to CFY rats in a single
dose at 313 ppm (1000 mg/m 3 ), 24 hours/day on GDs 9–14, resulting in statistically significant
Benzene VCCEP Submission
March 2006
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