126.96.36.199.1 Pregnant or lactating animals:
Information on distribution in pregnant or lactating rats is presented first followed by other species. Studies including oral exposures are summarized before those with parenteral exposures.
Takahashi and Oishi (2000) examined disposition and placental transfer of bisphenol A in F344 rats. Rats were orally administered 1000 mg/kg bw bisphenol A (>95% purity) in propylene glycol on gestation day (GD) 18 (GD 0=day of vaginal plug). Rats were killed at various time points between 10 min and 48 hr after bisphenol A dosing. At each time point, 2–6 dams and 8–12 fetuses obtained from 2–3 dams were analyzed. Blood was collected from dams and kidneys, livers, and fetuses were removed for measurement of bisphenol A concentrations by HPLC. Results are summarized in Table 23. Study authors noted the rapid appearance of bisphenol A in maternal blood and organs and in fetuses. Concentrations of bisphenol A at 6 hr following dosing were 2% of peak concentrations in maternal blood and 5% of peak concentrations in fetuses. It was noted that in fetuses, area under the time-concentration curve (AUC) was higher and mean retention time, variance of retention time, and terminal half-life were longer than in maternal blood.
Table 23. Toxicokinetic Endpoints for Bisphenol A in Rats Dosed With 1000 mg/kg bw Bisphenol A on GD 18a
|Mean retention time, hr||10.6||29.3||12.0||20.0|
|Variance in retention time, hr squared||203||657||227||419|
|Half-life, hr|| || || || |
| From 20–40 min||0.0952||0.178||0.245||0.55|
| From 40 min–6 hr||2.58||1.75||2.98||1.60|
| From 6–48 hr||4.65||No data||No data||173|
Dormoradzki et al. (2003) examined metabolism, toxicokinetics, and embryo-fetal distribution of bisphenol A in rats during 3 different gestation stages. Sprague–Dawley rats were gavaged with bisphenol A (99.7% purity)/radiolabeled 14C-bisphenol A (98.8% radiochemical purity) at 10 mg/kg bw. Bisphenol A was administered to 1 group of non-pregnant rats and 3 different groups of pregnant rats on GD 6 (early gestation), 14 (mid gestation), or 17 (late gestation). GD 0 was defined as the day that sperm or a vaginal plug were detected. Blood, urine, and feces were collected at multiple time points between 0.25 and 96 hr post-dosing. It appears that most and possibly all samples were pooled. Four rats in each group were killed at 96 hr post-dosing. Maternal organs, 6 embryos or fetuses/dam (when possible), and placentas were collected. Samples were analyzed for radioactivity and bisphenol A and/or bisphenol A glucuronide by HPLC/liquid scintillation spectrometry.
In all groups, 90–94% of radioactivity was recovered. Elimination of bisphenol A and its metabolites is discussed in Section 188.8.131.52. At 96 hr following dosing, low percentages of the dose were present in carcass (∼1–6%) and tissues such as brain, fat, liver, kidney, ovary, uterus, and skin. The only quantifiable data in placentas and fetuses at 96 hr were obtained in the GD 17 group, and those samples contained 0.01–0.07% of the bisphenol A dose. Standard deviations for maternal and fetal tissues generally exceeded 50% of the mean. Study authors concluded that disposition of radioactivity was similar in pregnant and non-pregnant rats.
Toxicokinetic data obtained from plasma profiles are summarized in Table 24. The authors stated that there was high inter-animal variability. The presence of two Cmax values was noted by the authors, and they stated that it was the result of enterohepatic circulation of radioactivity. Bisphenol A was not quantifiable in most plasma samples. Because bisphenol A glucuronide represented most (∼95–99%) of the radioactivity, plasma profiles for that metabolite were nearly identical to profiles for radioactivity.
Table 24. Toxicokinetic Data for Radioactivity in Pregnant and Non-Pregnant Rats Gavaged With 10 mg/kg bw 14C-bisphenol Aa
|Cmax1, mg eq/L||0.716||0.370||0.482||1.006|
|Cmax2, mg eq/L||0.171||0.336||0.211||0.278|
|Time to non-quantifiable level, hr||72||Not determined||72||96|
| 14C, mg-eq·hr/L||6.1||12.4||7.1||10.2|
| Bisphenol A glucuronide, mg-eq·hr/L||5.8||12.3||6.8||9.7|
|Percent as bisphenol A glucuronide||95.1||99.2||95.8||95.1|
A second study was conducted by Dormoradzki et al. (2003) to measure bisphenol A and bisphenol A glucuronide concentrations in maternal and fetal tissues. Rats were gavaged with radiolabeled bisphenol A at 10 mg/kg bw on GD 11, 13, or 16. Blood was collected over a 24-hr period. Five rats/group/time period were killed at 0.25, 12, and 96 hr post-dosing. Maternal blood and organs, yolk sacs/placentas, and embryos/fetuses were removed for measurement of bisphenol A and bisphenol A glucuronide. Yolk sacs/placentas and fetuses were pooled at most time periods. Results are summarized in Table 25.
Table 25. Maternal and Fetal Concentrations of Bisphenol A Following Gavage Dosing of Dams With 10 mg/kg bw Bisphenol Aa
|GD 11, 0.2 mCi|
| 0.25 hr||1.060±0.258||0.041||0.062||<LODb||<LOD||<LOD|
| 12 hr||0.099±0.036||<LOD||<LOD||<LOD||<LOD||<LOD|
| 96 hr||NA||NA||<LOD||<LOD||<LOD||<LOD|
|GD 13, 0.2 mCi|
| 0.25 hr||0.868±0.189||0.078||0.036||0.019||<LOD||0.013|
| 12 hr||0.117±0.033||0.008||0.013||0.009||<LOD||<LOD|
| 96 hr|| ||Not analyzed due to insufficient radioactivity|| || || |
|GD 16, 0.2 mCi|
| 0.25 hr||1.768±0.783||0.485, 0.129c||0.223±0.104||0.166±0.069||0.031, 0.009c||0.122, 0.020c|
| 12 hr||0.174±0.045||<LOD||0.025±0.005||0.034±0.002||NA||NA|
| 96 hr|| ||Not analyzed due to insufficient radioactivity|| ||0.016||0.008|
|GD 16, 0.5 mCi|
| 0.25 hr||1.699±0.501||0.064±0.025||0.342±0.104||0.095±0.031||0.013±0.008||0.018±0.011|
At 0.25 hr following dosing, bisphenol A glucuronide concentrations in maternal plasma were similar in groups dosed on GD 11 and 13 but concentrations were 1.7–2 times higher in the group dosed on GD 16. At 12 hr post-dosing in all exposure groups, bisphenol A glucuronide concentrations in maternal plasma were reduced 7- to 11-fold from values observed at 0.25 hr. Levels of radioactivity in plasma were not sufficient for analysis at 96 hr post-dosing. Bisphenol A was detected in maternal plasma at 0.25 hr post-dosing in rats that were exposed to a higher radioactive concentration (0.5 mCi compared to 0.2 mCi) on GD 16; bisphenol A concentrations were 26.5-fold lower than bisphenol A glucuronide concentrations.
In animals dosed on GD 11, bisphenol A glucuronide was only detected in yolk sac/placenta at 0.25 hr post-dosing and the concentration was ∼17 times lower than the concentration detected in maternal blood for the same time period. With dosing on GD 11, bisphenol A glucuronide was not detected in embryos and bisphenol A was not detected in yolk sac/placenta or embryos. In animals dosed on GD 13, bisphenol A glucuronide was detected in yolk sac/placenta at 0.25 and 12 hr post-dosing and concentrations were 9–24-fold lower than those detected in maternal plasma for the same time period. Bisphenol A was also detected in yolk sac/placenta at 0.25 and 12 hr after dosing on GD 13 and concentrations were similar to those detected in the blood of 2 dams. A lower concentration of bisphenol A was detected in embryos of dams at 0.25 hr following dosing on GD 13, and bisphenol A was the only moiety detected in embryos. Following dosing on GD 16, bisphenol A glucuronide and bisphenol A were detected in yolk sac/placenta at 0.25 and 12 hr post-dosing. Concentrations of bisphenol A glucuronide in yolk sac/placenta were 7- to 8-fold lower than concentrations detected in maternal plasma. From 0.25 to 12 hr, concentrations of bisphenol A decreased 4.9-fold and concentrations of bisphenol A glucuronide decreased 9-fold. Mean concentrations of bisphenol A in yolk/sac placenta following exposure on GD 16 were similar to the blood concentration detected in 1 of 2 dams.
In yolk sac/placenta and fetuses of dams dosed with a higher level of radioactivity (0.5 mCi) on GD 16, bisphenol A glucuronide and bisphenol A were detected at 0.25 hr following dosing. Compared to concentrations detected in placenta, fetal concentrations of bisphenol A glucuronide were ∼26-fold lower and bisphenol A concentrations were 5-fold lower. Bisphenol A concentrations were lower than bisphenol A glucuronide concentrations by 3.6-fold in yolk sac/placenta and by 0.7-fold in fetuses. Study authors concluded that there is no selective affinity for bisphenol A or bisphenol A glucuronide by the yolk sac/placenta or embryo/fetus.
Kurebayashi et al. (2005) examined distribution of radioactivity in pregnant and lactating rats dosed with 14C-bisphenol A. Pregnant rats were orally dosed with 0.5 mg/kg bw 14C-bisphenol A on GD 12, 15, or 18. The rats were killed at 30 min or 24 hr following dosing (n=1/time period) and examined by whole-body radioluminography. Study authors noted that the distribution of label was nearly identical in dams at each gestation time point. At 30 min following dosing, the concentration of radioactivity in dam blood was ∼31–43 μg bisphenol A eq/L. The highest concentration of radioactivity was detected in maternal liver (∼219–317 μg bisphenol A eq/kg) and kidney (∼138–270 μg bisphenol A eq/kg); concentrations in other tissues (lung, ovary, placenta, skin, and uterus) were ∼10-fold lower. Fetuses, fetal membranes, and yolk sacs did not contain quantifiable levels of radioactivity at 30 min following maternal exposure at any gestation time point. At 24 hr following exposure of dams, radioactivity concentrations in blood (∼4–11 μg bisphenol A eq/L) were nearly 3–10-fold lower than values obtained at 30 min following exposure. Levels of radioactivity remained highest in liver. At 24 hr following exposure, radioactivity was only detected in fetuses and fetal tissues from dams dosed on GD 18. Radioactivity levels in fetuses or fetal tissues compared to maternal blood were ∼30% in fetuses, nearly equal in fetal membranes, and ∼5-fold higher in yolk sacs. Study authors concluded that there was limited distribution of radiolabel to fetuses.
In another study by Kurebayashi et al. (2005), a lactating rat was orally dosed with 0.5 mg/kg bw 14C-bisphenol A on PND 11 and caged with 5 neonatal rats for 24 hours. One male and one female neonatal rat were killed at the end of the 24-hr period and examined by whole-body radioluminography. The 3 remaining neonates were caged for 24 hr with a dam that was not exposed to bisphenol A. One male and one female neonate were then killed and examined by whole-body radioluminography. In pups killed immediately after being nursed by the lactating dam exposed to 14C-bisphenol A, most of the radioactivity was detected in intestinal contents (∼30–46 μg bisphenol A eq/kg) and lower levels were found in gastric contents and urinary bladder (<10 μg bisphenol A eq/kg). After being nursed for 24 hr by a dam that was not exposed to bisphenol A, radioactivity was only detected in intestinal contents and the level was ∼20–40% of that measured in pups examined immediately after being nursed by dams receiving 14C-bisphenol A.
An additional 3 lactating dams were dosed with 0.5 mg/kg bw 14C-bisphenol A on PND 11 for examination of radioactivity in plasma and milk over a 48-hr period. Table 26 summarizes toxicokinetic endpoints for radioactivity in milk and plasma. Study authors concluded that there was significant secretion of 14C-associated radioactivity into milk.
Table 26. Toxicokinetic Endpoints for Radioactivity in Lactating Rats Orally Administered 0.5 mg/kg bw 14C-Bisphenol A on PND 11a
|Elimination half-life, hr||26||31|
|AUC (0–48 hr), μg-eq·hr/L)||156||689|
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 Figure3of 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 ∼34 ppb [μg/L] in maternal plasma and 11 ppb [μg/kg] in fetuses. At 3 hr after dosing, bisphenol A concentrations were ∼10% 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 14C-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, Table3of 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 (≤0.02%). Low percentages of the radioactive dose were also detected in milk (≤0.0020%), blood (∼0.006%), plasma (∼0.01%), and fat (≤0.004%). 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 > blood > milk. The major radioactivity peak in 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 <0.01% of the maternal dose. Radioactivity levels in pups tended to increase over time. From 2–24 hr following exposure, mean±SD radioactivity levels rose from 44±24 to 78±11 μg 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 184.108.40.206. 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 ∼3 μg/L following storage of that water in plastic containers. Bisphenol A concentration in feed was ∼40 μg/kg. Results for maternal and fetal tissues are summarized in Table 27, 28. 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.
Table 27. Bisphenol A Concentrations in Maternal and Pup Samples During Lactation in Rats Gavaged With Bisphenol Aa
| Serum||PND 21|| ||3±0||4±0||11±4|
| Milk||PND 10|| ||28±9||8±21||8±3|
| ||PND 14|| ||255±78||205±7||185±50|
| Serum||PND 10||Female||4||10||23|
| || ||Male||15||5||7|
| ||PND 14||Female||5||4||3|
| || ||Male||4||5||4|
| ||PND 21||Female||9||3||9|
| || ||Male||14||9||20|
| Liver||PND 10||Female||13||12||17|
| || ||Male||9||9||14|
| Liver||PND 14||Female||22||100||18|
| || ||Male||45||14||16|
| ||PND 21||Female||60||70||37|
| || ||Male||69||9||60|
Table 28. Toxicokinetic Endpoints for Bisphenol A in Pregnant Rats iv Dosed With 2 mg/kg bw Bisphenol Aa
|Elimination half-life, hr||2.5±0.9||2.2±0.8||2.2±0.8||3.9±3.1|
|Mean residence time, hr||3.0±1.1||2.0±0.5||3.0±0.9||5.6±4.7|
|Tmax, hr||No data||0.1±0.1||0.6±0.3||0.3±0.2|
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 (>99.7% 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 220.127.116.11. 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 5 min after injection, 50% of total bisphenol A 20 min after injection, and ∼10% of total bisphenol A 6 hr after the injection. The half-life of free bisphenol A in the dam's blood was 0.34 hr, and the half-life of total bisphenol A was 0.58 hr. Bisphenol A in fetal tissues peaked 20–30 min after maternal injection at 4.0 mg/kg in placenta, 3.4 mg/kg in fetal liver, and 2.4 mg/kg in remaining fetal tissues. Peak maternal blood bisphenol A had been 3.8 mg/L shortly after injection.
Rapid distribution of bisphenol A was observed in placenta, fetus, and amniotic fluid. Bisphenol A concentrations in placenta and fetus remained higher than those in maternal serum over most of the sampling period. Amniotic fluid contained the lowest concentration of bisphenol A. Decay curves in amniotic fluid, fetus, and placenta paralleled decay curves in maternal serum. Transfer rate constants and clearance rates are summarized in Table 29. Transfer rate constants were greater in the direction of amniotic fluid to fetus or placenta than in the opposite direction. The elimination rate constant and clearance rate from the fetal compartment were much lower than for the maternal central compartment. The clearance rate from placenta to fetus was higher than clearance rate from fetus to placenta. The authors calculated that 65.4% of the bisphenol A dose was delivered to the fetus, 33.2% to the maternal central compartment, and 1.4% to amniotic fluid. According to the study authors, the low transfer rate from the fetal to amniotic compartment suggested minimal fetal excretion of unchanged bisphenol A through urine and feces into the amniotic fluid. They also noted that the small fetal compartment transfer constant compared to the relative fetal–placental transfer constant indicated minimal metabolism by the fetus. Authors estimated that 100% of bisphenol A was eliminated from the fetus via the placental route and concluded that fetal elimination represents 0.05% of total elimination from the maternal–fetal unit.
Table 29. Intercompartmental Transfer and Clearances in Pregnant Rats Following Intravenous Bisphenol Aa
|Maternal central to maternal tissue||3.4±2.6||38.2±26.5|
|Maternal tissue to maternal central||1.7±1.3||50.2±36.7|
|Maternal central to placental||0.7±0.5||8.3±5.4|
|Placental to maternal central||23.6±14.7||2.2±1.3|
|Placental to fetal||46.4±29.2||4.1±2.1|
|Fetal to placental||22.8±28.0||7.6±6.0|
|Fetal to amniotic fluid||0.00001±0.00002||0.00001±0.00001|
|Amniotic fluid to fetal||14.0±21.0||0.8±1.1|
|Amniotic fluid to placental||7.9±6.7||0.7±0.7|
|Placental to amniotic fluid||1.0±1.3||0.1±0.1|
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 5 min after injection, 50% of total bisphenol A 20 min after injection, and ∼10% of total bisphenol A 6 hr after the injection. The half-life of free bisphenol A in the dam's blood was 0.34 hr, and the half-life of total bisphenol A was 0.58 hr. Bisphenol A in fetal tissues peaked 20–30 min after maternal injection at 4.0 mg/kg in placenta, 3.4 mg/kg in fetal liver, and 2.4 mg/kg in remaining fetal tissues. Peak maternal blood bisphenol A had been 3.8 mg/L shortly after injection.
Yoo et al. (2001) examined mammary excretion of bisphenol A in rats. At 4–6 days postpartum, 4–6 lactating female Sprague–Dawley rats/group were i.v. injected with bisphenol A at 0.47, 0.94, or 1.88 mg/kg bw and then infused with bisphenol A over a 4-hr period at rates of 0.13, 0.27, or 0.54 mg/hour. Blood samples were collected at 2, 3, and 4 hr, and milk was collected at 4 hr following initiation of infusion. Before collection of milk, rats were injected with oxytocin to increase milk production. HPLC was used to measure bisphenol A concentrations in serum. Differences in data for mean systemic clearance were analyzed by analysis of variance (ANOVA). Results are summarized in Table 30. The study authors noted extensive excretion of bisphenol A into milk, with milk concentrations exceeding serum concentrations. No significant differences were reported for systemic clearance rates between the 3 doses. Steady state concentrations of bisphenol A in maternal serum and milk increased linearly according to dose.
Table 30. Toxicokinetic Endpoints in Lactating Rats Infused With Bisphenol Aa
|Systemic clearance, mL/min/kg||119.2±23.8||142.4±45.3||154.1±44.6|
|Steady state serum bisphenol A concentration, ng/mL||66.1±15.5||120.0±34.7||217.1±65.0|
|Steady state milk bisphenol A concentration, ng/mL||173.1±43.3||317.4±154.4||493.9±142.2|
Kabuto et al. (2004) reported bisphenol A concentrations in mice indirectly exposed to bisphenol A during gestation and lactation. The focus of the study was oxidative stress; more details are presented in Section 3.2.7. Six ICR mouse dams were given drinking water containing 1% ethanol vehicle or bisphenol A at 5 or 10 μg/L. [Based on the reported water intake of 5 mL/day and an assumed body weight of 0.02 kg (USEPA,1988), it is estimated that bisphenol A intakes in mice at the start of pregnancy were 0.0013 and 0.0025 mg/kg bw/day.] Mice gave birth about 3 weeks following mating and pups were housed with dams for 4 weeks. [Based on an assumed body weight of 0.0085 kg and assumed water intake rate of 0.003 L/day (USEPA,1988), it is estimated that intake of bisphenol A in weanling males was 0.0018 and 0.0035 mg/kg bw/day.] At 4 weeks of age, male pups were killed and a GC/MS technique was used to measure bisphenol A concentrations in brain, kidney, liver, and testis in an unspecified number of control pups and in four pups from the 10 μg/L group. Study authors reported that they could not detect bisphenol A in control pups. In pups from the 10 μg/L group, the highest concentration of bisphenol A was detected in kidney (∼24 μg/kg wet weight), followed by testis (∼20 μg/kg wet weight), brain (∼18 μg/kg wet weight), and liver (∼11 μg/kg wet weight).
Zalko et al. (2003) examined metabolism and distribution of bisphenol A in pregnant CD-1 mice. A series of studies was conducted in which mice were treated with 3H-bisphenol A (>99.9% purity)/unlabeled bisphenol A (>99% purity). Mice were exposed to different regimens; biological samples examined included blood, liver, fat, gall bladder, uterus, ovaries, digestive tract and contents, urine, and feces. In the first exposure scenario, mice were s.c. injected with 0.025 mg/kg bw labeled/unlabeled bisphenol A on GD 17; three animals/time period were examined at 0.5, 2, and 24 hr following dosing. In the second exposure scenario, 2 mice/group were s.c. injected with 50 mg/kg bw bisphenol A on GD 17 and killed 24 hr following dosing. In the third scenario, 3 non-pregnant female mice/group were “force-fed” a single oral dose of 0.025 mg/kg bw bisphenol A; urine and feces were collected over 24 hr, and animals were killed at 24 hr. Biological samples were analyzed by scintillation analysis, HPLC, MS, and/or nuclear magnetic resonance.
In pregnant mice injected with 0.025 mg/kg bw/day bisphenol A and examined 24 hr later, 85.68% of the radioactivity was recovered. The highest percentages of radioactivity were detected in the digestive tract and contents (∼45%) and feces (∼21%). Less radioactivity was detected in the litter (∼4%), liver (∼2%), bile (∼2%), urine (∼6%), and carcass (∼3%). Blood, ovaries, uterus, placenta, amniotic fluid, fat, and cage washes each contained <1% of the radioactive dose. At 0.5 hr following dosing, levels of radioactivity were highest in uterus > liver > placenta > fetus > amniotic fluid > ovaries > carcass > blood. Radioactivity levels in tissues were lower by 24 hr following exposure. [Compared to radioactive levels detected in tissues at 24 hr, levels detected at 0.5 hr were ∼12-fold higher in uterus, 3-fold higher in liver, 8-fold higher in placenta, 3.5-fold higher in fetuses, 2-fold higher in amniotic fluid, and 3.5-fold higher in ovaries.] The only information provided for mice s.c. dosed with 50 mg/kg bw bisphenol A and examined 24 hr later was for radioactivity levels in organs; the highest levels (pg/g) were detected in uterus > blood > ovary > carcass > liver. Study authors stated that distribution of radioactivity was comparable in mice treated with 50 and 0.025 mg/kg bw bisphenol A. In the mice orally dosed with 0.025 mg/kg bw bisphenol A and examined 24 hr later, levels of radioactivity in blood, ovaries, and uterus were reported to be significantly lower [by ∼1–2 orders of magnitude] than levels in animals exposed by s.c. injection, but the level in the liver was not significantly different. There was significantly more residue in mouse carcass after oral than s.c. dosing (∼2.5 fold) (A. Soto, personal communication, March 2, 2007). No qualitative differences in metabolites were observed following oral or s.c. exposure. [Data were not shown by study authors.] Distribution of parent compound and metabolites detected in maternal and fetal tissues is summarized in Table 31. Further discussion on metabolites is included in Section 18.104.22.168.
Table 31. Qualitative Analysis of Maternal and Fetal Tissues Following Injection of Mice With 0.025 mg/kg bw Radiolabeled Bisphenol A on GD 17a
| 24||0.04±0.04||20|| ||0|| ||0||0.13±0.05||65|| ||0||15|
| 0.5|| ||0|| ||0||0.46±0.48||2||5.50±4.24||25||15.98±12.02||72||1|
| 24||0.01±0.01||1|| ||0||0.11±0.07||13||0.51±0.12||60||0.13±0.16||15||2|
Uchida et al. (2002) examined distribution of bisphenol A in pregnant mice and monkeys. On GD 17 (GD 0=day of vaginal plug), ICR mice were s.c. injected with bisphenol A 100 mg/kg bw in sesame oil vehicle. More than 3 mice/time point were killed at various points between 0.5–24 hr following injection. An untreated control group consisted of 6 mice. [Data were not presented for controls.] Maternal and fetal serum and organs were collected. Among organs collected were fetal uteri and testes, which were pooled. On GD 150, 2 Japanese monkeys (Macaca fuscata) were s.c. injected with 50 mg bisphenol A/kg bw and at 1 hr following injection, fetuses were removed by cesarean section. Two untreated fetuses were used as controls. Maternal and fetal serum and organs, not including reproductive organs, were collected from monkeys. Bisphenol A concentrations were measured by GC/MS in mouse and monkey samples.
In mice, bisphenol A was detected within 0.5 hr of exposure in all tissues examined, including placenta, maternal and fetal serum, liver, and brain, and fetal uterus, and testis. Bisphenol A concentrations were higher in fetal than maternal serum and liver. [Peak concentrations were observed within 0.5–1 hr in most tissues, with the exception of fetal brain (2 hr), and concentrations remained elevated for 1–6 hr, depending on tissue. More than one peak was observed in fetal serum, uterus, and testis.] In exposed monkeys, bisphenol A was found at the highest concentrations (15.6–72.50 mg/kg) in fetal heart, intestine, liver, spleen, kidney, thymus, muscle, cerebrum, pons, and cerebellum; bisphenol A concentrations in the same organs from control monkeys were measured at 3.70–22.80 mg/kg. Lower concentrations of bisphenol A were detected in umbilical cord and maternal and fetal serum of the exposed group (1.70–6.10 mg/kg) and control group (0.02–0.25 mg/kg). The study authors stated that the most likely source of bisphenol A in control monkeys was the feed, which was found to contain bisphenol A. The study authors concluded that the placental barrier does not protect the fetus from bisphenol A exposure.
Halldin et al. (2001) examined distribution of bisphenol A in quail eggs or hens. After injection of fertilized quail egg yolk sacs with 67 μg/g 14C-bisphenol A egg on incubation day 3, <1% of radioactivity was detected in embryos at incubation day 6 or 9. A similar finding was reported for diethylstilbestrol. At incubation day 6, no specific localization was observed in the embryo but in 10- and 15-day-old embryos a high amount of radioactivity was observed in liver and bile. [Low transfer of labeled bisphenol A to the egg was reported after oral or i.v. dosing of quail hens (with apparently 105 μg bisphenol A), but concentrations in eggs were not quantified by study authors.]
22.214.171.124.2 Non-pregnant and non-lactating animals:
Domoradzki et al. (2004), examined the effects of dose and age on toxicokinetics and metabolism of bisphenol A in rats. Neonatal and adult male and female Sprague–Dawley rats were gavaged with 14C-bisphenol A (∼99% radiochemical purity)/non-radiolabeled bisphenol A (99.7% purity). Three neonatal rats/age/sex/time period were dosed on PND 4, 7, and 21 with 1 or 10 mg/kg bw bisphenol A. Adult rats (11 weeks old) [number treated not specified] were dosed with 10 mg/kg bw bisphenol A. Blood samples were collected at various time points from 0.25–24 hr post-dosing in neonatal rats and from 0.25–96 hr in adult rats. Plasma samples were pooled on PND 4. Immature rats were killed at 24 hr post-dosing, and adult rats were killed at 96 hr post-dosing. Brain, liver, kidneys, skin, and reproductive organs were collected from neonatal rats. Levels of radioactivity, bisphenol A, and/or metabolites were analyzed in blood and tissue samples using HPLC and liquid scintillation spectrometry.
In neonatal and adult rats, radioactivity levels in plasma generally peaked within 0.25–0.75 hr. With the exception of 0.25 hr post-dosing on PND 4, when plasma radioactivity levels were ∼4-fold higher in males than females, plasma radioactivity levels were generally similar in male and female rats. At 24 hr post-dosing, plasma radioactivity levels were 4–100 times lower in all groups of neonatal rats. Trends were noted for decreasing radioactivity levels with increasing age. Information related to dose- and age-related effects on metabolism is presented in Section 126.96.36.199.
Toxicokinetic values for bisphenol A are listed in Table 32. Cmax and AUC values for bisphenol A decreased with increasing age, especially following dosing with 10 mg/kg bw. Bisphenol A concentrations were lower in adults than neonates. No patterns were observed for half-lives, and the authors stated that values in neonates may not have been reliable because bisphenol A concentrations were near the LOD at the end of the 24-hr observation period. Ratios of Cmax and AUC values for the 10 and 1 mg/kg bw doses were different at 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.
Table 32. Toxicokinetic Values for Bisphenol A in Rats Following Gavage Dosing With 1 or 10 mg/kg bwa
|Bisphenol A dose: 1 mg/kg bw|
| Tmax, hr||0.25||0.25||0.25||0.25||3||3|| || |
| Cmax, mg/L||0.03||0.06||0.04||0.08||0.005||0.006|| || |
| Half-life, hr||7.2||7.3||21.8||8.8|| || || || |
| AUC, mg·hr/L||0.2||0.1||0.1||0.1|| || || || |
|Bisphenol A dose: 10 mg/kg bw|
| Tmax, hr||0.25||0.25||0.25||0.25||1.5||1.5||0.25||0.75|
| Cmax, mg/L||48.3||10.2||1.1||1.4||0.2||0.2||0.024||0.063|
| Half-life, hr||17||6.7||11.4||8.5||4.3||6.6||“0”||“0”|
| AUC, mg·hr/L||23.1||7.2||1.9||1.7||1.1||1||“0”||“0”|
|Ratio of value at 10 to 1 mg/kg bw/day|
| Cmax||1610||170||27.5||17.5|| || || || |
| AUC||115.2||72||19||17|| || || || |
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 [∼2–6 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, ∼100% of the dose was represented by bisphenol A glucuronide.
Table 33. Toxicokinetic Values for Bisphenol A Glucuronide in Rats Following Gavage Dosing With 1 or 10 mg/kg bw Bisphenol Aa
|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||45||96||77||77|| || || || |
|Bisphenol A dose: 10 mg/kg bw|
| 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|
| AUCBPA-glucuronide/AUCBPA||3.5||7||31||36||55||56|| || |
|Ratio of value at 10 to 1 mg/kg bw/day|
| Cmax||10.1||4.2||3.3||9.4||13||9.8|| || |
| AUC||8.9||5.2||7.6||7.9||14.7||17|| || |
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.
Table 34. Distribution of Radioactivity to Tissues at 24 Hr Following Dosing With Radiolabeled Bisphenol Aa
|Females, 1 mg/kg bw|
|Brain||11.7||0.4|| ||6.7||0.2|| ||3.6||0.1|| |
|Liver||18||7.5|| ||7.9||7.1|| ||3.6||2.9|| |
|Kidney||18.1||9.4|| ||7.3||9.5|| ||5.0||3.0|| |
|Ovary||11.7||7.3|| ||6.0||3.5|| ||3.7||0.9|| |
|Uterus||7.4||8.3|| ||6.2||3.0|| ||3.4||1.0|| |
|Carcass||11.2||22.2|| ||10.0||16.6|| ||4.0||8.3|| |
|Plasma||19.5||9.4|| ||6.4||7.8|| ||3.6||3.5|| |
|Females, 10 mg/kg bw|
|Males, 1 mg/kg bw|
|Brain||14.1||0.3|| ||6.0||0.3|| ||3.4||0.1|| |
|Liver||19.7||6.1|| ||6.6||7.3|| ||3.7||3.2|| |
|Kidney||19.3||8.5|| ||7.0||8.6|| ||4.6||3.4|| |
|Testis||10.3||3.4|| ||5.7||2.0|| ||3.4||0.8|| |
|Carcass||11.1||22.2|| ||9.0||17.3|| ||4.1||9.0|| |
|Plasma||24.0||9.2|| ||6.6||7.7|| ||3.4||4.2|| |
|Males, 10 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 188.8.131.52. Adult male and female F344 rats were dosed with 14C-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 post-dosing, 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 Tmax was observed with s.c. dosing. Cmax and AUC values were lowest following oral administration. Time to non-quantifiable 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 route, as noted by approximate proportionate increases in Cmax and AUC values from the low to the high-dose. Toxicokinetics data for radioactivity in plasma are summarized in Table 36. Concentrations of radioactivity were dependent on exposure route and to a lesser extent, dose and sex. AUC values for radioactivity were lowest following oral exposure. Time to non-quantifiable concentration was longest following s.c. dosing. For most groups, Cmax 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 184.108.40.206.
Table 35. Toxicokinetic Endpoints for Bisphenol A in Blood Following Dosing of Rats by Gavage or Injectiona
| Tmax, hr||N/A||0.083||0.5||0.25||0.75||0.5|
| Cmax, mg/L, hrb||c||0.22±0.09||0.69±0.08||9.7±1.27||0.39±0.16||5.19±0.98|
| Time to non-quantifiable concentration, hr||0.083||0.75||8||12||18||24|
| AUC, mg · hr/L|| ||0.1||1.1||16.4||2.6||24.5|
| Tmax, hr||0.25||0.25||0.25||0.25||4||0.75|
| Cmax, mg/L, hrb||0.04±0.03||2.29±1.82||0.87±0.15||13.13±4.13||0.34±0.06||3.97±0.6|
| Time to non-quantifiable concentration, hr||1|| ||24||72||48||72|
| AUC, mg·hr/L||0.42||4.4||1.4||26.2||3.1||31.5|
Table 36. Toxicokinetics for Radioactivity Following Dosing of Rats with Bisphenol A Through Different Exposure Routesa
| Tmax, hr||0.25||0.25||0.5||0.25||1||0.75|
| Cmax, mg eq/L, hr||0.73±0.22||3.92±1.93||1.26±0.09||29.3±11.7||0.61±0.24||6.33±0.43|
| Time to non-quantifiable concentration, hr||72||72||96||96||96||144|
| AUC, mg-eq · hr/L||8.1||66.5||16.9||170||15.5||218|
| Tmax, hr||0.083||0.25||0.25||0.5||0.75||0.75|
| Cmax, mg eq/L, hr||1.82±0.66||28.33±8.64||2.27±0.19||67.81±7.33||0.52±0.06||5.66±0.95|
| Time to non-quantifiable concentration, hr||72||72||72||120||120||168|
| AUC, mg-eq·hr/L||9.54||94.9||15.3||247||21.6||297|
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 μg/L bisphenol A. Concentrations decreased to 700 μg/L within 1 hr, 100 μg/L within 2 hr, and non-detectable concentrations by 24 hr followingexposure. The apparent final elimination half-life was estimated at 38.5 hr. In rats gavaged with 10 mg/kg bw, an initial maximum blood concentration of 30 μg/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 μg/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 μg/L) and 3 hr (134 μg/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 bi-exponential 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.
Table 37. Toxicokinetic Values for Bisphenol A in Adult Rats Exposed to Bisphenol A Through the Intravenous or Oral Routea
|Distribution half-life, min||6.1±1.3|| |
|Terminal elimination half-life, hr||0.9±0.3||21.3±7.4|
|Systemic clearance, mL/min/kg||107.9±28.7|| |
|Steady-state volume of distribution, L/kg||5.6±2.4|| |
|Cmax, μg/L|| ||14.7±10.9|
|Tmax, hr|| ||0.2±0.2|
|Apparent volume of distribution, L/kg|| ||4273±2007.3|
|Oral clearance, mL/min/kg|| ||2352.1±944.7|
|Absolute oral bioavailability, %|| ||5.3±2.1|
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 220.127.116.11, fecal excretion was the main route of elimination for radioactivity following oral or i.v. dosing of rats with 0.1 mg/kg bw 14C-bisphenol A. A study describing biliary excretion and metabolites in bile is summarized in Section 18.104.22.168. Toxicokinetic endpoints were determined in a study in which blood was drawn from 3 male rats/group at various time points between 0.25–48 hr following oral gavage or i.v. dosing with 0.1 mg/kg bw bisphenol A. Results of the study are summarized in Table 38. Rapid absorption of radioactivity was observed following oral dosing. AUC values were significantly lower for oral than i.v. dosing. In a another study, rats were administered 14C-bisphenol A by i.v. injection and blood was collected 30 min later for determination of blood/plasma distribution and protein binding. At a blood radioactivity level of 80 nM [18 μg bisphenol A eq/L], preferential distribution to plasma was observed, with the blood/plasma ratio reported at 0.67. At radioactivity levels of 6–31 μg-eq/L (27–135 nM), plasma protein binding was reported at 95.4%. Additional studies reviewed by Teeguarden et al. (2005) reported plasma protein binding of bisphenol A at ∼90–95%. An additional study by Kurebayashi et al. (2003) compared metabolic patterns and excretion following exposure to a higher bisphenol A dose; that study is discussed inSection 22.214.171.124.
Table 38. Toxicokinetic Endpoints for 14C-Bisphenol A-Derived Radioactivity in Rats Exposed to 0.1 mg/kg bw 14C-Bisphenol A Through the Oral or I.V. Routea
|Tmax, hr|| ||0.38±0.10|
|Cmax, μg-eq/L|| ||5.5±0.3|
|Half-life-α, hr||0.59±0.09||No data|
|Absorbance rate, hr−1|| ||3.6±1.0|
|Volume of distribution, L/kg||27.0±0.7||No data|
|Total body clearance. L/hr/kg||0.522±0.011||0.544±0.049|
|Mean residence time, hr||51.7±2.4||No data|
| 0–6 hr||33.9±1.6||18.4±0.7b|
| 0–24 hr||79.3±3.3||60.0±7.1b|
| 0–48 hr||118±4||102±13b|
| 0–6 hr|| ||0.54|
| 0–24 hr|| ||0.76|
| 0–48 hr|| ||0.86|
| 0–∞|| ||0.97|
Kurebayashi et al. (2005) administered 14C-bisphenol A to adult male and female F344 rats (3/dose/sex) at doses of 0.020, 0.1, or 0.5 mg/kg bw orally or 0.1 or 0.5 mg/kg bw by i.v. injection. Plasma samples were analyzed for radioactivity over a 72-hr period to determine toxicokinetic endpoints. Results are summarized in Table 39. Study authors noted that the AUC was almost linearly correlated with dose. Several peaks were observed with oral or i.v. exposure, indicating enterohepatic cycling, according to the study authors. Study authors noted that substantially lower AUC values in females than in males following oral exposure could have resulted from lower absorption and/or a higher elimination rate. Distribution of radioactivity was evaluated 0.5, 24, and 72 hr following oral administration of 0.1 mg/kg bw bisphenol A to adult male and female Wistar rats (3/sex/time point). At 0.5 hr following exposure, most of the radioactivity (∼12–51 μg bisphenol A eq/kg) was found in kidney and liver. [A large amount of radioactivity was also reported for intestinal contents, but those data were not shown by the study authors.]. Lower amounts of radioactivity (∼2–7 μg bisphenol A eq/kg or L) were detected in adrenal gland, blood, lung, pituitary gland, skin, and thyroid gland of both sexes; uterus; and bone marrow, brown fat, and mandibular gland of males. In males,<μg bisphenol A eq/kg was detected in skeletal muscle and testis. Radioactivity was non-quantifiable in brain and eye of both sexes; epididymis, prostate gland, and heart of males; and bone marrow, brown fat, skeletal muscle, and mandibular gland of females. At ≥24 hr following exposure, radioactivity was detected primarily in only kidney, liver, and intestinal contents, with the exception of ∼3 μg bisphenol A eq/L detected in blood of males at 24 hr following dosing. Study authors noted that elimination of radioactivity from some tissues appeared to occur more rapidly in females than in males. Distribution in pregnant animals was also examined and is described in Section 126.96.36.199.1.
Table 39. Toxicokinetic Endpoints for Plasma Radioactivity in Rats Dosed With 14C Bisphenol Aa
| Elimination half-life, hr||78±52||18±3||21±3||19±2||21±3|
| AUC, μg-eq·hr/L||36±6||178±44||663±164||266±46||865±97|
| Apparent absorption, %||82||81||60|| || |
| Elimination half-life, hr||20±7||22±13||18±8||13±3||16±2|
| AUC, μg-eq·hr/L||14±5||99±19||500±43||190±45||1029±81|
| Apparent absorption, %||35||50||50|| || |
Kabuto et al. (2003) reported distribution of bisphenol A in mice. Male ICR mice were i.p. dosed with bisphenol A at 0, 25, or 50 mg/kg bw/day for 5 days and killed 6 hr following the last dose. Bisphenol A concentrations in tissues of animals from the high-dose group were determined by GC/MS. In mice of the high-dose group, the highest concentrations of bisphenol A were detected in kidney (∼2.02 mg/kg wet weight) and body fat (∼1.25 mg/kg wet weight). Lower concentrations of bisphenol A (≤0.42 mg/kg wet weight or mg/L) were detected in brain, lung, liver, testis, and plasma.
Kurebayashi et al. (2002) examined the toxicokinetics of a low bisphenol A dose in Cynomolgus monkeys following gavage or i.v. dosing. Three adult male and female monkeys were dosed with 0.1 mg/kg bw 14C-bisphenol A (99% radiochemical purity)/non-radiolabeled bisphenol A [purity not reported]. Monkeys were dosed by i.v. injection on Day 1 of the study and by gavage on Day 15 of the study. Urine and feces were collected for 7 days post-dosing. Blood samples were collected at various time points from 0.083–72 hr following i.v. dosing and for 0.25–71 hr after oral dosing. Binding to plasma protein was determined at some time points over 0.25–4 hr. Samples were analyzed by liquid scintillation counting and HPLC. Following oral or i.v. exposure, the percentage of radioactivity recovered in excreta and cage washes was 81–88% over a 1-week period. As discussed in greater detail in Section 188.8.131.52, most of the radioactivity was excreted in urine and very little was excreted in feces. Toxicokinetic endpoints are summarized in Table 40. Based on the toxicokinetic values, study authors concluded that absorption of bisphenol A following oral exposure was rapid and high, and terminal elimination half-lives of bisphenol A/metabolites were longer following i.v. than oral exposure. As discussed in more detail in Section 184.108.40.206, glucuronide compounds were the major metabolites detected in urine, and higher percentages of the radioactive dose in plasma were represented by bisphenol A following i.v. than oral dosing.
Table 40. Toxicokinetic Endpoints for Radioactivity in Male and Female Cynomolgus Monkeys Exposed to 14C-Bisphenol A Through IV Injection or by Gavagea
| AUC, μg-eq·hr/L||377±85||382±96|
| Volume of distribution, L/kg||1.58±0.11||1.82±0.41|
| Half-life, hr||13.5±2.6||14.7±2.1|
| Total body clearance, L/hr/kg||0.27±0.05||0.28±0.08|
| Mean residence time, hr||5.93±0.91||6.68±0.72|
| AUC, μg-eq·hr/L||265±74||244±21|
| Tmax, hr||1.00±0.87||0.33±0.14|
| Cmax. μg-eq/L||104±85||107±37|
| Half-life. hr||9.63±2.74||9.80±2.15|
Negishi et al. (2004b) compared toxicokinetics of bisphenol A in female F344/N rats, Cynomolgus monkeys, and Western chimpanzees. Bisphenol A was administered by oral gavage and s.c. injection at doses of 10 or 100 mg/kg bw/day to rats and monkeys and 10 mg/kg bw to chimpanzees. Three rats/dose/time point were killed before and at various times between 0.5 and 24 hr following bisphenol A administration. Three monkeys/group and 2 chimpanzees were first exposed orally and 1 week later by s.c. injection. In monkeys, blood samples were drawn before and at various times from 0.5–24 hr after dosing. In chimpanzees, blood was drawn before and at multiple time points between 0.25–24 hr following dosing. Bisphenol A was measured in serum by ELISA, and toxicokinetics endpoints were determined. Results are summarized in Table 41. The study authors noted that the bioavailability of bisphenol was lowest in rats<chimpanzees<monkeys following exposure through either route. In most cases, bisphenol A was not detected in rat serum following oral administration of the 10 mg/kg bw dose. In all species, higher bioavailability was observed with s.c. than oral dosing.
Table 41. Toxicokinetic Endpoints for Bisphenol A by ELISA in Rats, Monkeys, and Chimpanzeesa
|Rat (data presented as mean±SD)|
| Cmax, μg/L|| ||872±164||580±398||3439±679|
| Tmax, hr|| ||1.0||0.5||1.0|
| AUC0–4 h, μg·hr/L|| ||1912±262||506±313||9314±2634|
| AUC0–24 h, μg·hr/L|| ||3377±334||1353±462||23,001±6387|
|Monkey (data presented as mean±SD)|
| Cmax, μg/L||279±±920||57,934±1902||5732±525||10,851±3915|
| Tmax, hr||0.7±0.2||2.0±0.0||0.7±0.2||2.0±0.0|
| AUC0–4 h, μg·hr/L||3209±536||15,316±5856||14,747±2495||48,010±11,641|
| AUC0–24 h, μg·hr/L||3247±587||39,040±10,738||52,595±8951||189,627±21,790|
|Chimpanzee (data presented for 2 animals)|
| Cmax, μg/L||325; 96||2058; 1026||Dose not administered|
| Tmax, hr||0.5; 0.5||2.0; 2.0|| || |
| AUC0–4 h, μg·hr/L||491; 235||5658; 3109|| || |
| AUC0–24 h, μg·hr/L||1167; 813||21,141; 12,492|| || |
In a subsequent report (Tominaga et al., 2006), these authors noted that ELISA may overestimate bisphenol A concentrations due to non-specific binding. They reported measurements by LC-MS/MS in animals evaluated using the same study design [possibly the same specimens reported previously]. These results are summarized in Table 42. The authors proposed that primates, including humans, may completely glucuronidate orally-administered bisphenol A on its first pass through the liver and excrete it in the urine whereas bisphenol A remains in the rat for a more extended period due to enterohepatic recirculation. They suggested that the rat may not be a good model for human bisphenol A kinetics.
Table 42. Toxicokinetic Endpoints for Bisphenol A by LC-MS/MS in Rats, Monkeys, and Chimpanzeesa
|Rat (data presented as mean±SD)|
| Cmax, μg/L||2.1±1.6||746±80||47.5±10.6||2631±439|
| Tmax, hr||0.7±0.3||0.8±0.3||0.5±0.0||1.2±0.8|
| t1/2, hr||not calculated||3.2±0.7||not calculated||4.5±0.7|
| AUC0–4 h, μg·hr/L||4.2b||1542±200||43.2±9.7||6926±1071|
| AUC0–24 h, μg·hr/L||7.2b||1977±182||350±294||15,576±2263|
|Monkey (data presented as mean±SD)|
| Cmax, μg/L||11.5±2.2||4213±3319||28.6±3.9||7010±3045|
| Tmax, hr||1.0±0.9||1.7±0.6||3.3±1.2||2.7±1.2|
| t1/2, hr||8.9±3.0||3.8±0.8||4.5±0.7||12.9±3.6|
| AUC0–4 h, μg·hr/L||21.4±6.1||8828±4309||85.3±18.6||19,981±7567|
| AUC0–24 h, μg·hr/L||42.5±7.3||18,855±3870||350±13||79,796±21,750|
|Chimpanzee (data presented as mean for 2 animals)|
| Cmax, μg/L||5.5||703||Dose not administered|
| Tmax, hr||0.8||1.0|| || |
| t1/2, hr||6.8||4.2|| || |
| AUC0–4 h, μg·hr/L||13.3||2148|| || |
| AUC0–24 h, μg·hr/L||33.1||6000|| || |