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

glucuronidating bisphenol A, and possible involvement
of other liver isoforms was noted (Yokota et al., 1999).
There are some data indicating that glucuronidation
capacity is very limited in fetuses and lower in immature
than adult animals. Little-to-no UGT2B activity toward
bisphenol A was detected in microsomes of rat fetuses;
activity of the enzyme increased linearly following birth
(Matsumoto et al., 2002). In an in vitro study comparing
clearance of bisphenol A by hepatic microsomes from
rats of different ages, activity was lower in microsomes
from fetuses than in those from immature animals and
adults [reviewed in (European-Union, 2003)]. As noted in
Table 63, immature rats are capable of glucuronidating
bisphenol A, but activity appears to increase with age.
One study demonstrated that neonatal rats were able to
glucuronidate a larger fraction of a lower (1 mg/kg bw)
than higher (10 mg/kg bw) bisphenol A dose (Domoradzki
et al., 2004).
Kurbayashi et al. (2005) evaluated fetal and maternal
rat bisphenol A during different stages of pregnancy.
Bisphenol A labeled with carbon-14 was administered
p.o. to male and female Fischer (F344) rats at relatively
low doses (20, 100, and 500 mg/kg), and i.v. injected at 100
and 500 mg/kg). 14 C-bisphenol A (500 mg/kg) was also
administered orally to pregnant and lactating rats to
examine the transfer of radioactivity to fetuses, neonatal
rats, and milk (Table 64). Radioluminographic determination
using phosphor imaging plates was employed to
achieve highly sensitive determination of radioactivity.
Absorption ratios of radioactivity after three oral doses
were high (35–82%); parent 14 C- bisphenol A in the
circulating blood was quite low, however, suggesting
considerable first-pass effect. After an oral dose of
100 mg/kg 14 C- bisphenol A, the radioactivity was
distributed and eliminated rapidly, but remained in the
intestinal contents, liver, and kidney for 72 hr. The major
metabolite in the plasma and urine was bisphenol A
glucuronide, whereas most of the bisphenol A was
excreted with the feces as free bisphenol A. A second
peak in the time-course of plasma radioactivity suggested
enterohepatic recirculation of bisphenol A glucuronide.
There was limited distribution of 14 C- bisphenol A
to the fetus and neonate after oral administration to the
dam. Significant radioactivity was not detected in fetuses
on GD 12 and 15. On GD 18, however, radioactivity was
BISPHENOL A
233
detected in the fetal intestine and urinary bladder 24 hr
after oral dosing of 14 C- bisphenol A to the dam. The
distribution pattern of radioactivity in pregnant rats was
essentially the same as that in non-pregnant female rats.
The distribution levels were dose-dependent in most of
the tissues. There was limited distribution of 14 Cbisphenol
A to the fetus. Radioactivity in fetal tissues
was undetectable except on GD 18 in the fetal urinary
bladder and intestine. On GD 18, the amount of radioactivity
in fetal tissues at 24 hr was about 30% that in
maternal blood, and the yolk sac contained a much
higher level of radioactivity than the maternal blood. The
Expert Panel thought these differences were a consequence
of the routes of administration, i.v. or p.o.,
because only trace amounts of parent bisphenol A dosed
orally appeared in the plasma.
The major metabolite of bisphenol A is the glucuronide
conjugate. Another metabolite that has been commonly
detected in urine is bisphenol A sulfate. Excretion
patterns for bisphenol A are summarized in Table 65.
As noted in Table 65, the major elimination routes
for bisphenol A in rodents are feces and bile; a
lower percentage of the dose is eliminated through
urine. The major compound detected in feces is
bisphenol A and the major compound detected in bile
and urine is bisphenol A glucuronide. Excretion
patterns and metabolic profiles observed in rodents
dosed orally or parenterally with low (o1 mg/kg bw/
Table 67
Toxicokinetic Values for Radioactive Dose in Pregnant
Rats (Total Bisphenol A) a
Endpoint Value
Cmax1/ Cmax2, mg eq/L 370–1006/211–336
Tmax1/ Tmax2, hr 0.25/12–24
Time to non-quantifiable concentration, hr 72–96
AUC 14 C, mg –eq � hr/L 7100–12,400
AUC Bisphenol A glucuronide, 6800–12,300
mg –eq � hr/L
a Dormoradzki et al. (2003).
Dams were gavaged with 10 mg/kg bw/day on GD 6–10, 14–18,
or 17–21.
GD, gestation day.
Table 66
Toxicokinetic Values for Free Bisphenol A in Pregnant Rats and Fetuses
Dose Endpoint Maternal Fetal Reference
1000 mg/kg bw orally on GD 18 Cmax, mg/L 14,700 9220 Takahashi and Oishi (2000)
10 mg/kg bw orally on GD 19 Concentration 1-hr post-dosing, mg/L 34 11 Miyakoda et al. (1999)
2 mg/kg bw i.v. on 1 day between GD 17–19 Cmax, mg/L 927.3 794 Shin et al. (2002)
1000 mg/kg bw orally on GD 18 Tmax, min 20 20 Takahashi and Oishi (2000)
2 mg/kg bw i.v. on 1 day between GD 17–19 Tmax, hr No data 0.670.3 Shin et al. (2002)
1000 mg/kg bw orally on GD 18 AUC, mg � hr/L 13,100 22,600 Takahashi and Oishi (2000)
2 mg/kg bw i.v. on 1 day between GD 17–19 AUC, mg � hr/L 905.5 1964.7 Shin et al. (2002)
1000 mg/kg bw orally on GD 18 Mean retention time, hr 10.6 20.0 Takahashi and Oishi (2000)
1000 mg/kg bw orally on GD 18 Variance in retention time, hr 2
203 419 Takahashi and Oishi (2000)
2 mg/kg bw i.v. on 1 day between GD 17–19 Mean residence time, hr 3.0 3.0 Shin et al. (2002)
1000 mg/kg bw orally on GD 18 Half-life, hr: Takahashi and Oishi (2000)
From 20–40 min 0.0952 0.55
From 40 min–6 hr 2.58 1.60
From 6–48 hr 4.65 173
2 mg/kg bw i.v. on 1 day between GD 17–19 Elimination half-life, hr 2.5 2.2 Shin et al. (2002)
Birth Defects Research (Part B) 83:157–395, 2008