(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

gestation, and number of live and dead pups at birth and sex distribution. No effects were
observed in pup survival. Reduced body weight and absolute organ weight trends were
observed in 21-day-old pups from the 30- and 300-ppm groups, but the only statistically
significant result was reduced liver weight in the female pups of 300-ppm dams. The authors
did not assign a lowest-observed-adverse-effect level (LOAEL) or a no-observed-adverse-effect
level (NOAEL); the observed effects were limited to relatively minor effects in the pups and were
not related to reproduction, so the NOAEL for reproduction is 300 ppm. The pup results are
discussed further in the developmental toxicity section (see Section 6.2.3.2). Two earlier
Russian studies (Gofmekler 1968 and Vozovaya 1975, 1976) also investigated the effect of
benzene exposure on reproductive performance, although these studies have previously been
determined to be unreliable due to poor documentation (ECB 2003). Gofmekler (1968) exposed
female rats to 3–210 ppm benzene, 24 hours/day, 10–15 days prior to mating, and for 3 weeks
during gestation. A complete absence of litters was observed in the top dose females (210
ppm), but not at lower concentrations (3 to 20 ppm). Differences in individual organ weights of
the dams were indicated for all exposure levels, but no impairment of weight or malformations
were reported in the newborns. There is insufficient information to explain the absence of litters
in the 210-ppm dose group. Vozovaya (1975, 1976) exposed female rats to benzene to 0, 116,
or 559 ppm (0, 370, 1783 mg/m 3 ) for 4 months prior to mating and through gestation, although
no information is available on the daily and weekly duration of exposure. Decreased pup body
weight was reported in both exposure groups, but no malformations were observed at 116 ppm
or 559 ppm. Given the questionable reliability of both the Gofmekler (1968) and Vozovaya
(1975, 1976) studies, the primary study available to assess reproductive performance in animals
is the Kuna 1992 study. While there were limited pup effects observed in the Kuna 1992 study,
and reduced liver weight in female pups of top dose dams, the study suggests that benzene
exposures up to 300 ppm did not affect female reproductive parameters.
The ability of benzene exposure to affect male reproductive processes can be inferred from an
inhalation dominant lethal study in which male rats were exposed to benzene at concentrations
of 1–300ppm for 10 weeks (through one cycle of spermatogenesis). Following this exposure,
the male rats were then mated to untreated female rats, and the pregnant female rats were
sacrificed on GD 16 for determination of dominant lethal effects. No effects on reproductive
performance were reported, although 2/20 males exposed to 300 ppm had microscopically
observed testicular lesions (API, 1980). The usefulness of dominant lethal studies in
understanding male reproductive toxicity is limited, in that sperm parameters are not
determined, and the pregnant female rats are not allowed to deliver, so the viability of the
offspring is not known.
Evaluations of reproductive organs in subchronic inhalation studies include a publication by Wolf
(1956) that reported moderately increased testicular weight in rats exposed to 6600 ppm
(21,084 mg/m 3 ) benzene for 13 weeks but not in rats exposed to 88 ppm (287 mg/m 3 ) or 2200
ppm (7,172 mg/m 3 ) for 30 weeks, 4400 ppm (14,344 mg/m 3 ) for 5 weeks, or to 9400 ppm
(30,644 mg/m 3 ) over 1–19 days. Male guinea pigs exposed to 88 ppm for approximately 9.6
months had slight increases in testicular weight, but exposure for 4 weeks had no effect.
Rabbits showed slight degeneration of seminiferous tubules after exposure to 88 ppm for
approximately 8.5 months. A 13-week inhalation study (Ward et al., 1985) employed Sprague
Dawley rats and CD-1 mice exposed to benzene concentrations of 0, 10, 30, and 300 ppm (0,
32, 96, and 958 mg/m 3 ). Body weights of both species were unaffected, but mice exposed to
300 ppm exhibited statistically significant decreases in testes weight at days 28, 56, and 91;
decreased testes/body-weight ratio at days 56 and 91; and testicular atrophy (7/10 mice),
decrease in spermatozoa in epididymal ducts (6/10 mice), and minimal to moderate increase in
abnormal sperm forms (9/10 mice) at terminal sacrifice after 91 exposures. Four in 10 female
Benzene VCCEP Submission
March 2006
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