Monograph on the Potential Human Reproductive and ... - OEHHA

196 CHAPIN ET AL.
Table 36
Toxicokinetics for Radioactivity Following Dosing of Rats with Bisphenol A Through Different Exposure Routes a
Exposure route and doses (mg/kg bw)
Endpoint 10 oral 100 oral 10 i.p. 100 i.p. 10 s.c. 100 s.c.
Males
T max, hr 0.25 0.25 0.5 0.25 1 0.75
Cmax, mg eq/L, hr 0.7370.22 3.9271.93 1.2670.09 29.3711.7 0.6170.24 6.3370.43
Time to non-quantifiable 72 72 96 96 96 144
concentration, hr
AUC, mg-eq � hr/L 8.1 66.5 16.9 170 15.5 218
Females
Tmax, hr 0.083 0.25 0.25 0.5 0.75 0.75
Cmax, mg eq/L, hr 1.8270.66 28.3378.64 2.2770.19 67.8177.33 0.5270.06 5.6670.95
Time to non-quantifiable 72 72 72 120 120 168
concentration, hr
AUC, mg-eq � hr/L 9.54 94.9 15.3 247 21.6 297
a Pottenger et al. (2000).
Table 37
Toxicokinetic Values for Bisphenol A in Adult Rats
Exposed to Bisphenol A Through the Intravenous or Oral
Route a
Bisphenol A dosing
0.1 mg/kg 10 mg/kg
Endpoint bw, i.v. bw, gavage
Distribution half-life, min 6.171.3
Terminal elimination 0.970.3 21.377.4
half-life, hr
AUC, mg � hr/L 16.173.2 85.6733.7
Systemic clearance, 107.9728.7
mL/min/kg
Steady-state volume of 5.672.4
distribution, L/kg
Cmax, mg/L 14.7710.9
Tmax, hr 0.270.2
Apparent volume of 427372007.3
distribution, L/kg
Oral clearance, mL/min/kg 2352.17944.7
Absolute oral bioavailability, % 5.372.1
Data presented as mean7SD.
a Yoo et al. (2001).
following oral exposure. Time to non-quantifiable concentration
was longest following s.c. dosing. For most
groups, C max and AUC values were proportionate across
doses within the same exposure route. A second part of
the study examined metabolites and is summarized in
Section 2.1.2.3.
Upmeier et al. (2000) examined toxicokinetics in rats
exposed to bisphenol A through the oral or i.v. route.
Ovariectomized DA/Han rats (130–150 g bw) were
exposed to bisphenol A by i.v. injection with 10 mg/kg
bw or oral gavage with 10 or 100 mg/kg bw. Blood was
collected from treated rats at multiple time points until
2 hr following i.v. dosing and 3 hr following oral dosing.
Three to five rats were sampled during each time period.
To reduce stress, only some of the rats were sampled at
each time point. In control animals, blood was collected
2 hr following dosing with vehicle. Bisphenol A
concentrations in plasma were measured by GC/MS.
Dosing with 10 mg/kg bw i.v. resulted in a maximum
plasma concentration of 15,000 mg/L bisphenol A. Concentrations
decreased to 700 mg/L within 1 hr, 100 mg/L
within 2 hr, and non-detectable concentrations by 24 hr
followingexposure. The apparent final elimination halflife
was estimated at 38.5 hr. In rats gavaged with 10 mg/
kg bw, an initial maximum blood concentration of 30 mg/
L was obtained at 1.5 hr. A decrease in bisphenol A blood
concentration at 2.5 hr was followed by a second peak of
40 mg/L at 6 hr, leading study authors to conclude that
enterohepatic cycling was occurring. The same patterns
of bisphenol A concentrations in blood were observed
following gavage dosing with 100 mg/kg bw. Peak
concentrations were observed at 30 min (150 mg/L) and
3 hr (134 mg/L) following exposure. According to the
study authors, the differences in peak concentrations
observed between the two doses suggested lower
bioavailability at the high-dose than at the low dose.
Oral bioavailability of bisphenol A was estimated at
16.4% at the low dose and 5.6% at the high-dose.
Yoo et al. (2001) examined toxicokinetics of a low i.v.
dose and a higher gavage dose of bisphenol A in male
rats. Five adult male Sprague–Dawley rats/group were
administered bisphenol A by i.v. injection at a dose of
0.1 mg/kg bw or by gavage at a dose of 10 mg/kg bw.
Multiple blood samples were collected until 3 hr following
i.v. dosing and 24 hr following gavage dosing. HPLC
was used to measure bisphenol A concentrations in
serum. Route-specific differences in mean systemic
clearance were analyzed by Student t-test. Results are
summarized in Table 37. The study authors noted biexponential
decay of serum bisphenol A concentrations
following i.v. dosing, significantly longer elimination
half-life with oral than i.v. exposure, and low oral
bioavailability of bisphenol A.
Kurebayashi et al. (2003) conducted a series of studies
to examine toxicokinetics and metabolism of bisphenol A
in adult F344N rats exposed through the oral or i.v. route.
In these studies, radioactivity levels were measured by
scintillation counting. Bisphenol A or its metabolites
were quantified by HPLC, electrospray ionization/MS,
or nuclear magnetic resonance. As discussed in greater
detail in Section 2.1.2.4, fecal excretion was the main
Birth Defects Research (Part B) 83:157–395, 2008