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

Table 26
Toxicokinetic Endpoints for Radioactivity in Lactating
Rats Orally Administered 0.5 mg/kg bw 14 C-Bisphenol A
on PND 11 a
Endpoint Milk Maternal plasma
Cmax, mg-eq/L 4.46 27.2
T max, hr 8 4
Elimination half-life, hr 26 31
AUC (0–48 hr), mg-eq � hr/L) 156 689
a Kurebayashi et al. (2005).
Miyakoda et al. (1999) examined placental transfer of
bisphenol A in rats. Wistar rats were administered an
oral dose of bisphenol A (99% purity) at 10 mg/kg bw on
GD 19. Blood was collected and fetuses were removed at
1, 3, and 24 hr following dosing. Bisphenol A concentrations
were measured in plasma and fetuses by GC/MS.
[A statement in Figure 3 of the study indicated that
values were the means of 5 or 7 experiments; it is
possible the authors meant that 5 or 7 dams were
dosed.] Concentrations of bisphenol A peaked in
maternal plasma and fetuses within 1 hr of dosing, with
bisphenol A concentrations measured at B34 ppb [lg/L]
in maternal plasma and 11 ppb [lg/kg] in fetuses. At 3 hr
after dosing, bisphenol A concentrations were B10% of
peak concentrations in maternal plasma and 40% of peak
concentrations in fetuses. At 24 hr post-dosing, bisphenol
A concentrations in fetuses were detected at 70% of peak
value and concentrations in fetuses were more than twice
the concentrations in maternal plasma. Study authors
concluded that bisphenol A is rapidly transferred to the
fetus and tends to remain longer in fetuses than in
maternal blood.
Snyder et al. (2000) examined the toxicokinetics of
bisphenol A in lactating rats. On PND 14, lactating CD
rats were gavaged with 100 mg/kg bw 14 C-bisphenol A.
Milk, blood, and organs were collected from 2–4 dams/
group at 1, 8, 24, or 26 hr after dosing. [While the text
indicates collection of samples at 26 hr, Table 3 of the
study indicates collection at 24 hr. The collection time
reported in the study table was used when there were
discrepancies between text and table.] Animals were
injected with oxytocin before milk collection. Radioactivity
in pup carcasses was measured at 2, 4, 6, and
24 hr following exposure of dams; 8–16 pups/time
period were examined [pup data does not appear to be
analyzed by litter]. Samples were analyzed by scintillation
counting, HPLC, and/or nuclear magnetic resonance.
At 1 and 8 hr following exposure, the highest
percentage of the radioactive dose was detected in
intestine with contents (75–83%). Among the other
organs examined, the highest percentage of the radioactive
dose was detected in liver (0.38–0.74%) and much
lower percentages were detected in kidney and lung
(r0.02%). Low percentages of the radioactive dose were
also detected in milk (r0.0020%), blood (B0.006%),
plasma (B0.01%), and fat (r0.004%). Compared to
earlier time periods, radioactivity levels were lower at
24 hr post-dosing (26% of the dose detected in intestine
and contents), but distribution was similar. At all 3
sampling time points, radioactivity levels were highest in
plasma 4 blood 4 milk. The major radioactivity peak in
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
189
plasma was represented by bisphenol A glucuronide at 1,
8, and 26 hr following exposure. Bisphenol A glucuronide
also represented the major radioactive peak
detected in milk. Radioactivity levels in pups amounted
to o0.01% of the maternal dose. Radioactivity levels in
pups tended to increase over time. From 2–24 hr
following exposure, mean7SD radioactivity levels rose
from 44724 to 78711 mg bisphenol A eq/pup.
Yoshida et al. (2004) compared bisphenol A concentrations
in rats and their offspring during the lactation
period. The main focus of the study was developmental
toxicity, which is discussed in Section 3.2.3.2. In the
distribution study, Donryu rats (12–19/group) were
gavaged with bisphenol A at 0 (carboxymethylcellulose
solution), 0.006, or 6 mg/kg bw/day from GD 2 to the
day before weaning (21 days post-delivery). Bisphenol A
concentrations were measured in maternal and pup
serum, milk, and pup liver by GC/MS on PND 10, 14,
and/or 21. Milk samples were obtained from pup
stomachs. Pup serum and liver samples were pooled.
Two to six dams/litter were examined in each dose
group and time period. Samples of tap water, drinking
water from plastic containers, and feed were measured
for bisphenol A content by HPLC. Bisphenol A was not
detected in fresh tap water but was detected at B3 mg/L
following storage of that water in plastic containers.
Bisphenol A concentration in feed was B40 mg/kg.
Results for maternal and fetal tissues are summarized
in Table 27. Bisphenol A concentrations in the serum of
high-dose-dams were significantly elevated compared to
the control group on PND 21. No other significant
differences were observed in bisphenol A concentrations
in samples between treated and control groups.
Kim and Huang (2003) used an HPLC method to
measure bisphenol A concentrations in rat dams and
their offspring. Dams were gavaged with bisphenol A
(499.7% purity) at doses of 0 (corn oil vehicle), 0.002,
0.020, 0.200, 2, or 20 mg/kg bw/day on GD 7–17. Dams
and offspring were killed at 21 days following parturition,
and serum was collected for measurement of
bisphenol A. Development effects observed in this study
are summarized in Section 3.2.1.1. Bisphenol A was not
detected in the serum of dams at the two lowest doses.
Respective concentrations of bisphenol A in the serum of
dams at the 3 highest doses were 0.900, 0.987, and
1.00 mg/L. In offspring, bisphenol A was not detected in
serum at the 3 lowest doses. At the 2 highest doses, the
respective concentrations of bisphenol A in offspring
were 0.69 and 0.74 mg/L in males and 0.71 and 0.82 mg/
L in females.
Shin et al. (2002) examined elimination of bisphenol A
from maternal–fetal compartments of rats. On 1 day
between GD 17 and 19, four Sprague–Dawley rats were
i.v. injected with 2 mg/kg bw bisphenol A. Amniotic
fluid, placenta, and fetuses were collected at multiple
intervals between 5 min and 8 hr following injection.
Bisphenol A concentrations in samples were measured
by HPLC. Transfer rate constants and clearance rates
were determined using a five-compartment model
consisting of maternal central, maternal tissue, placental,
fetal, and amniotic fluid compartments. Toxicokinetic
findings are summarized in Moors et al. (2006) evaluated
the kinetics of bisphenol A in pregnant rats on GD 18
after a single i.v. dose of 10 mg/kg bw. Unconjugated
bisphenol A represented almost 80% of total bisphenol A