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

parameters were examined at Day 30, 60, and 90 of the
study. Ophthalmoscopic examinations were conducted
before initiation of and following 90 days of dosing. The
rats were killed and organs weighed. Adrenals, pituitary,
ovaries, and thyroid were weighed following fixation in
10% neutral buffered formalin. Histopathological examinations
were conducted in tissues from 10 rats/sex/group
in the control and high-dose groups. Organs histologically
examined included prostate, uterus, testis, and ovary.
Statistical analyses included w 2 test with Yates correction,
Fisher exact probability test, Mann–Whitney U-test, ANO­
VA, t-test, and Dunnett multiple comparison test.
In parental rats, bisphenol A exposure did not affect
general behavior, appearance, or survival. Mean body
weight of males in the 1000 ppm group was 6% lower
than control males. Food intake was increased [by B7–
11%, no dose–response] in females of all dose groups.
Bisphenol A exposure had no effect on estrous cyclicity
or gestation length [data were not shown], male or
female fertility, number of pups/litter, or pup survival
Body weights of pups in the 750 ppm group were
significantly higher [by B10%] compared to controls
on PND 21, but the study authors did not consider the
effect to be treatment-related.
In the F 1 offspring, a slight decrease in body weight
gain was observed for males in the 750 ppm group. [At
the end of the study, body weights of males in the
750 ppm group were B7% less than controls]. Food
intake was similar in treated and control groups.
Ophthalmoscope examinations did not reveal any treatment-related
effects. Although mean blood urea nitrogen
levels were slightly lower and mean serum glutamicoxaloacetic
transaminase values were sporadically increased
in treated rats, the study authors noted that the
values were within physiological ranges. There were no
effects on hematological or urinalysis parameters. Some
significant organ weight changes were noted by the
study authors, but they stated that the biological
significance of the effects was not known. [There did
not appear to be dose–response relationships for any
organ weight change.] The study authors stated that no
compound-related lesions were observed in organs,
including reproductive organs.
Strengths/Weaknesses: The use of multiple dose levels
(going down to fairly low exposure levels) is a plus, as is a
breeding phase. Weaknesses include the limited number of
animals per group, discarding of the parental animals
without examination, the fact that not all F1 animals were
examined at least for structural effects, the lack of close
examination of F 1 animals for reproductive effects (cyclicity
and sperm measures), and the use of the conventional ‘‘topdown’’
pathology evaluation, wherein the lower dose
groups were examined only if effects were noted in the
high-dose. The study has not been peer-reviewed.
Utility (Adequacy) for CERHR Evaluation Process:
For what it is, this study is adequate and of limited
utility for the evaluative process, showing no gross
changes in the structure of a limited number of tissues in
a limited number of F 1 animals, exposed from preconception.
This study was not designed to find unusual
effects or non-linear dose–response relationships or to
address the issue of low-dose functional responses or
non-linear responses.
Ema et al. (2001), supported by the Japanese Ministry
of Health and Welfare, examined developmental toxicity
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
249
endpoints, in a 2 generation rats study described in detail
in Section 4.2.3.1. Two generations of rats were gavaged
with 0, 0.0002, 0.002, 0.020, or 0.200 mg/kg bw/day
bisphenol A (99.9% purity) before and during mating
and throughout the gestation and lactation period. These
doses were based on previous studies that found effects
at 0.002 and 0.020 mg/kg bw/day. There were some nondose-related
and sporadic effects, but the study authors
concluded that none of the effects were related to
bisphenol A treatment. Bisphenol A exposure did not
adversely affect prenatal or postnatal growth or survival,
developmental landmarks, anogenital distance, or age of
puberty. In adult animals exposed to bisphenol A during
development, there was no evidence of adverse effects
on reproductive endpoints such as fertility, estrous
cyclicity, or sperm counts. Prostate and other male
reproductive organ weights were unaffected.
Strengths/Weaknesses: Strengths of this study were
the thoroughness of the evaluation, the size of the dose
range, the large number of animals, the litter-based
analysis, and the verification of the dosing solution. A
minor weakness is the lack of a positive control group,
which leaves a question about the ability of this group of
rats to respond.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation process.
Tyl et al. (2002b), supported by The Society of the
Plastics Industry, Inc., reported some developmental
toxicity effects in a multigeneration bisphenol A study
in Sprague–Dawley rats that is reported in detail in
Section 4.2.3.1. In that study, F 1, F2, and F3 rats were
exposed to bisphenol A [99.70%-99.76% pure] indirectly
during gestation and lactation and directly through feed
after weaning. Dietary doses were 0, 0.015, 0.3, 4.5, 75,
750, or 7500 ppm, and target intakes were B0.001, 0.02,
0.30, 5, 50, and 500 mg/kg bw/day. At the 7500 ppm dose
there were fewer pups and live pups/litter and body
weight gain of pups was lower during the lactation
period. Delayed puberty in both males and females of the
7500 ppm group was most likely related to reduced body
weights according to the study authors. Bisphenol A
exposure during development did not increase the
weight of the prostate in adult rats. Although some
decreases in epididymal sperm concentration and
daily sperm endpoints were each observed in 1 generation
of males from the high-dose group, the study authors
concluded there were no treatment-related effects on
sperm endpoints or reproductive function. The study
authors identified an offspring and reproductive NOAEL
of 750 ppm (B50 mg/kg bw/day). A systemic NOAEL
for adult rats was identified at 75 ppm (B5 mg/kg bw/
day) by the study authors; therefore, bisphenol A was not
considered a selective developmental toxicant.
Strengths/Weaknesses: This study has numerous
strengths, including the quality and number of the
endpoints evaluated, the number of dose groups and
generations examined, and the confirmation of dosing
solutions. This study incorporated screening-level endpoints
within the context of a multigeneration study. As
such, it addresses gross issues but does provide helpful
data regarding the NOAEL.
Utility (Adequacy) for CERHR Evaluation Process:
This study is adequate and of high utility for the
evaluation process.