(VCCEP) Tier 1 Pilot Submission for BENZENE - Tera

proposed that transplacental effect of benzene and some of its metabolites (e.g., phenol), and
conversion of benzene to benzene-oxide at the site of activity could be responsible for
embryotoxicity. Benzene can also damage maternal circulation and cause bone marrow
depression.
Iba et al. (2001) treated lactating adult mice with a single i.p. dose of 800 mg/kg [14C] benzene,
and their 2-day-old neonates were either treated similarly or nursed by treated dams.
Comparison of their ability to metabolize benzene to urinary products or reactive intermediates
was assessed by covalently bound benzene derivatives in whole blood or liver DNA. Metabolite
fractions were identified in urine of i.p.-treated neonates by high-performance liquid
chromatography. Results showed that excretable, as well as reactive, metabolites of benzene
were formed substantially by the neonatal mouse, and that the extent of bioactivation is
comparable in the adult and the suckling neonate.
6.2.4.4 Developmental Neurotoxicity
No studies were available, with the exception of a trial by Ungváry and Donath (1984), who
reported that the abundant noradrenergic fibers normally found in the ovary and uterus of
pregnant rats decreased with benzene exposure at 1500 mg/m 3 , 8 hours/day on GD 8–10. The
authors suggested a differential toxic effect on postganglionic neurons with a potential for
embryotoxicity.
6.2.4.5 Summary
Overall, a substantive body of data is available in several species to demonstrate that benzene
at doses above 47 ppm can induce developmental toxicity, sometimes at maternally toxic levels,
but does not cause malformations. Transplacentally, benzene also affects hematopoiesis and
clastogenicity in fetuses and may contribute to carcinogenesis in neonatal animals. According
to the EU Benzene Risk Assessment draft (ECB 2003), the absence of teratogenic effects,
fetotoxicity primarily at maternally toxic high doses and negative results in the available fertility
study (Kuna et al., 1992), no further testing is needed.
Although benzene has been demonstrated to induce neurotoxic effects in adult animals and
humans after short-term exposure to relatively high concentrations, there are no studies in the
published literature that evaluate neurotoxic potential during fetal or neonatal development.
6.2.5 Repeated-Exposure Toxicity in Experimental Animals
The categories of subchronic toxicity, chronic toxicity, and carcinogenicity are used to classify
and describe the types of effects that are observed in test animals or humans over a continuum.
The test distinctions are relative to time elapsed and are arbitrary; the time periods for the
categories actually overlap. Cancer studies usually include the standard parameters for
determining general toxicity as well as tumorigenesis. For the following discussion, the
descriptor subchronic toxicity is used for animal studies of 28 days or longer but less than 1 year
in duration, and the term chronic for studies of one year or longer in duration.
6.2.5.1 Subchronic Toxicity
Repeat-dose toxicity studies were conducted primarily by the oral and inhalation routes, but
several studies have been performed by the intraperitoneal (i.p.) and intravenous (i.v.) routes.
Also, benzene has been used as a vehicle and control substance in evaluating the toxicity of
Benzene VCCEP Submission
March 2006
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