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

BISPHENOL A 237
Table 70
Maternal and Developmental Effects in Rats Exposed to Bisphenol A a
Dose, mg/kg bw/day
Endpoint 100 300 1000 BMD10 BMDL10 BMD1SD BMDL1SD
Dams
No. pregnant
Body weight gain
Corrected body weight
Food intake on GD 4
No. fetal deaths
No. early resorptions
Post-implantation losses
Fetuses
No. live /litter
Male body weight
Female body weight
Ossification
2
2
2
2
2
2
2
2
2
2
2
2
k35%
k14%
k24%
2
2
2
2
k14%
2
2
k30%
k52%
k15%
k57%
m6.5-fold
m6-fold
m11-fold
k36%
k20%
k21%
k
a Kim et al. (2001b).
m,k Statistically significant increase, decrease compared to controls; 2 No statistically significant effect compared to controls.
solution concentrations were verified. Pregnant animals
were weighed during the study. Rats were killed on GD
20. Liver and uterus were weighed, and corpora lutea
and implantation sites were examined. Fetuses were
sexed, weighed, and examined for viability and external,
visceral, and skeletal malformations. Data were analyzed
by Bartlett test for homogeneity of variance, ANOVA
and/or William multiple comparison, Dunnett, or Fisher
exact probability tests. [Data were presented and
analyzed on a per litter basis.]
An unexpectedly high number of dams (7 of 27) died
in the 1280 mg/kg bw/day group, with most deaths
occurring in the second set of animals. Because of the
high death rate, the study authors decided not to
evaluate data in the 1280 mg/kg bw/day group. Clinical
signs that occurred most frequently in dams from the
640 mg/kg bw/day group included lethargy, piloerection,
pica, rough coat, wet urogenital area, weight loss,
and alopecia. Significant and dose-related decreases in
maternal body weights were observed during the entire
gestation period and thus were not confined to the GD 6–
15 treatment period in rats from the 160, 320, and
640 mg/kg bw/day groups. Body weight corrected for
gravid uterine weight was also decreased in all three
dose groups. Effects on maternal body weight were most
pronounced during the treatment period. [During the
treatment period, dam body weights were 35, 53, and
54% lower in the 160, 320, and 640 mg/kg bw/day
groups than in control groups; estimated benchmark
doses 4 in mg/kg bw/day were BMD10 113, BMDL10 94,
4 Benchmark doses are used commonly in a regulatory setting; however,
they are used in this study when the underlying data permit their
calculation, and are only supplied to provide one kind of description of
the dose–response relationship in the underlying study. Calculation of a
benchmark dose in this report does not mean that regulation based on the
underlying data is recommended, or even that the underlying data are
suitable for regulatory decision-making. The BMD10 is the benchmark
dose associated with a 10% effect, estimated from a curve fit to the
experimental data. The BMDL10 represents the dose associated with the
lower 95% confidence interval around this estimate. Unless otherwise
indicated, BMD values in this report were calculated using a power model
for continuous data and a probit model for dichotomous data using
Environmental Protection Agency (EPA) Benchmark Dose Software
version 1.3.2.
Birth Defects Research (Part B) 83:157–395, 2008
178
631
168
827
821
1278
929
456
439
152
490
147
13
14
394
348
339
328
379
566
313
978
980
982
694
682
304
424
257
585
584
713
497
490
BMD1SD 416, BMDL1SD 321.] Despite this large effect on
maternal body weight, there were no effects on numbers
of implantation sites or resorptions, gravid uterine
weight, or liver weight. The numbers of litters available
for evaluation in the control and 160, 320, and 640 mg/kg
bw/day dose group were 23, 26, 24, or 29. There were no
significant effects on fetal body weight or viability,
percentage males/litter, or malformed fetuses/litter.
Study authors concluded that bisphenol A was not
teratogenic in rats at doses that cause maternal toxicity.
Strengths/Weaknesses: This study used adequate
sample sizes to evaluate the effects of GD 6–15 exposure
on maternal body weight during gestation and on
implantation and resorption sites/dam, fetal body
weight, and fetal viability to GD 20. Strengths are the
verification of dosing solutions, use of GLP, adequate n,
sensitive evaluation of soft and hard-tissue structures.
Weaknesses include no postnatal examination, as well as
the absence of data from the 1280 mg/kg bw/day group,
the absence of a no-effect dose. The absence of effects on
fetal endpoints despite marked reductions in maternal
body weight corrected for gravid uterine weight warrants
the appropriate conclusion that bisphenol was not
teratogenic when based on GD 20 data. Further, a gross
visceral exam is likely insensitive to certain abnormalities
of the reproductive tract and brain, as noted above.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation process.
Kim et al. (2001b), support not indicated, examined
the effects of prenatal bisphenol A exposure on developmental
toxicity in rats. Sprague–Dawley rats were fed
commercial rodent chow (Jeil Feed Co., Daejon, Korea)
and housed in polycarbonate cages; no information was
provided about bedding. Twenty dams/group were
gavaged with 0 (corn oil vehicle), 100, 300, or 1000 mg/
kg bw/day bisphenol A [purity not provided] on GD 1–
20 (GD 0 5 first 24 hr after detection of vaginal sperm or
plug). Dose selection was based on the results of a
preliminary study that demonstrated maternal and
developmental toxicity at doses Z400 mg/kg bw/day
and a lack of effect at doses r200 mg/kg bw/day.
Endpoints examined in dams during the study were