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

194 CHAPIN ET AL.
Table 33
Toxicokinetic Values for Bisphenol A Glucuronide in Rats Following Gavage Dosing With 1 or 10 mg/kg bw
Bisphenol A a
Age at exposure and sex
PND 4 PND 7 PND 21 Adult
Endpoint Male Female Male Female Male Female Male Female
Bisphenol A dose: 1 mg/kg bw
Tmax, hr 0.75 0.75 0.75 0.25 0.25 0.25
Cmax, mg/L 1.3 1.5 2 1.1 0.8 0.8
Half-life, hr 26.1 24.2 6.6 6.4 4.2 4.1
AUC, mg � hr/L 9 9.6 7.7 7.7 4.1 3.3
AUCBPA-glucuronide/AUCBPA
Bisphenol A dose: 10 mg/kg bw
45 96 77 77
Tmax, hr 1.5 1.5 1.5 0.75 0.75 0.75 0.25 0.25
Cmax, mg/L 13.1 6.3 6.6 10.3 10.4 7.8 0.6 0.7
Half-life, hr 7.3 9.8 9.1 8.4 4.4 4.4 22.5 10.8
AUC, mg � hr/L 80 50.3 58.9 60.9 60.3 56.1 31.5 9.8
AUC BPA-glucuronide/AUC BPA 3.5
7 31 36 55 56
Ratio of value at 10 to 1 mg/kg bw/day
C max 10.1 4.2 3.3 9.4 13 9.8
AUC 8.9 5.2 7.6 7.9 14.7 17
Data missing from table cells were not determined.
a Domoradzki et al. (2004).
each age and generally decreased with age. Plasma
bisphenol A concentrations were very low in adults
dosed with 10 mg/kg bw; therefore, few data were
available.
Toxicokinetic values for bisphenol A glucuronide are
listed in Table 33. Peak plasma concentrations of bisphenol
A glucuronide were 9–22 times higher in
neonates than adult rats dosed with 10 mg/kg bw
bisphenol A. AUC values for bisphenol A glucuronide
were also higher in neonates than adults [B2–6 times
higher]. In neonates dosed with 1 mg/kg bw, AUC
values and elimination half-lives for bisphenol A
glucuronide decreased with age. Ratios of Cmax and
AUC values for the 10 and 1 mg/kg bw doses were
nearly proportional. In adults dosed with 10 mg/kg bw,
bisphenol A glucuronide concentrations peaked at
0.25 hr and secondary peaks were observed at 18 and
24 hr. In neonates dosed with 10 mg/kg bw, concentrations
of bisphenol A glucuronide peaked at 0.75–1.5 hr
and then bisphenol A glucuronide was eliminated in an
apparently monophasic manner. Half-lives of elimination
were shorter in neonates compared to adults. In neonatal
rats, the bisphenol A glucuronide represented 94–100%
of the 1 mg/kg bw dose and 71–97% of the 10 mg/kg
bw/day dose. In adult rats, B100% of the dose was
represented by bisphenol A glucuronide.
Half-life and AUC data for bisphenol A-derived
radioactivity in organs of neonatal rats are summarized
in Table 34. Radioactivity was distributed to all organs
and dose-related increases were observed. The study
authors noted lower concentrations in brain than in other
tissues. [Levels of radioactivity in reproductive organs
compared to those in plasma varied at each evaluation
period but were usually within the same or one order of
magnitude lower.] With the exception of males dosed
with 10 mg/kg bw bisphenol A, half-lives decreased with
age. There were some disproportionate increases in ratios
of AUC at 10 and 1 mg/kg bw.
The study authors concluded:
* Metabolism of bisphenol A to its glucuronide conjugate
occurred as early as PND 4 in rats;
* Dose-dependent differences occurred in neonatal rats,
as noted by a larger fraction of the lower dose being
metabolized to the glucuronide; and
* There were no major sex differences in metabolism or
toxicokinetics of bisphenol A.
Pottenger et al. (2000) examined the effects of dose and
route on metabolism and toxicokinetics of bisphenol A in
rats. Information focusing on toxicokinetics is summarized
primarily in this section, while metabolic data are
summarized primarily in Section 2.1.2.3. Adult male and
female F344 rats were dosed with 14 C-bisphenol A (99.3%
radiochemical purity)/non-radiolabeled bisphenol A
(99.7% purity) at doses of 10 or 100 mg/kg bw by oral
gavage or i.p. or s.c. injection. Blood was collected at
multiple time points between 0.083 and 168 hr postdosing,
and excreta were collected for 7 days. Animals
were killed 7 days post-dosing. Blood, brain, gonads,
kidneys, liver, fat, skin, uterus, and carcass were
analyzed by liquid scintillation counting and HPLC.
Some samples were analyzed by HPLC/electrospray
ionization/MS.
Toxicokinetic endpoints for bisphenol A in blood are
summarized in Table 35. Study authors noted that
concentration-time profiles of bisphenol were dependent
on dose, exposure route, and sex. The longest T max was
observed with s.c. dosing. C max and AUC values were
lowest following oral administration. Time to nonquantifiable
concentrations of bisphenol A was longest
following s.c. exposure. The only sex-related difference
was a higher Cmax value in females than males following
oral dosing. In most cases, bisphenol A toxicokinetics
were linear across doses within the same administration
Birth Defects Research (Part B) 83:157–395, 2008