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

248 CHAPIN ET AL.
100–151 g for females) were given feed containing bisphenol
A [purity not specified] at 0, 1000, 3000, or
9000 ppm for 17 weeks. [It was not clear how long before
mating that the dosing was started or if dosing was
continued through the gestation and lactation periods.]
The European Union (2003) estimated bisphenol A intake
at 0, 70, 200, or 650 mg/kg bw/day in males and 0, 100,
300, or 950 mg/kg bw/day in females. F0 rats were mated
at B100 days of age and assessed for fertility. F 1 pups
were counted and weighed at birth and on PND 21 (day of
birth not defined). Fifteen male and female F 1 rats/group/
sex that were exposed in utero were selected for a 13-week
feeding study and were fed diets containing the same
concentration of bisphenol A as their parents. F1 rats were
weighed and observed for clinical signs. Hematological,
clinical chemistry, and urinalysis parameters were examined
in 5 rats/sex/group in the control and 2 highest dose
groups at 1, 2, and 3 months of F 1 exposure. Ophthalmoscopic
examinations were conducted at 3 months of F 1
exposure. After 13 weeks of dosing, the F1 rats were killed
and necropsied. Organs were weighed and fixed in 10%
neutral buffered formalin. Included among organs
weighed were testis and ovary. Histopathological examinations
were conducted in tissues from 10 rats/sex/
group in the control and high-dose group. Included
among organs histologically examined were prostate,
uterus, testis, and ovary. Statistical analyses included w 2
test with Yates correction, Fisher exact probability test,
Mann–Whitney U-test, ANOVA, t-test, and Dunnett
multiple comparison test.
Fertility was unaffected in F0 rats. Body weight gain
was lower in F0 rats from the 3000 and 9000 ppm groups.
Body weight at Week 17 followed the same patterns as
body weight gain [6–7% decrease in the 3000 ppm group
and 12–18% decrease in the 9000 ppm group compared
to controls]. There were no differences in food intake.
[Statistical significance for body weight effects was not
reported. It was not clear if statistical analyses were not
conducted or if the effects did not attain statistical
significance.]
There were no effects on number of F 1 pups/litter or
survival of pups. Pup birth weights in the 9000 ppm
group were slighter decreased but were said to be within
normal range. Body weight gains on PND 21 were
slightly decreased in pups from the 3000 and 9000 ppm
dose groups. Body weights on PND 21 were significantly
lower in pups from the 3000 and 9000 ppm groups [7 and
12% lower compared to controls; benchmark dose
analysis not conducted because variances not reported].
One male F 1 rat in the control group and 2 female F 1 rats
in each of the 3000 and 9000 ppm group died during the
study. Post-weaning body weight gain was lower in
females from all dose group and in males from the 3000
and 9000 ppm dose groups. Body weight at week 13
followed the same patterns as body weight gain [13%
decrease in the 1000 ppm group, 11–17% in the
3000 ppm group, and 22–24% decrease in the 9000 ppm
group compared to controls]. Food intake was decreased
in females from all dose groups and in males from the
9000 ppm group. Examination by ophthalmoscopy revealed
no treatment-related effects. No treatment-related
effects were observed for hematology, biochemistry, or
urinalysis. No changes in organ weights or gross or
histopathological lesions were considered treatmentrelated.
The study authors noted increases in mean
weights of spleen, brain, thyroid, and adrenals in the
treated groups but concluded that the effects resulted
from decreased body weight. [With the exception of
PND 21 pup weights, there was no discussion of
statistical significance for effects observed in F 1 rats. It
was not clear if statistical analyses were not conducted
or if statistical significance was not attained.]
Strengths/Weaknesses: This study is a conventional,
state-of-the-art-at-the-time two-generation toxicity study.
The inclusion of a breeding period and a second
generation are strengths. Weaknesses are magnified in
hindsight: these include the limited number of animals
examined, the lack of close examination of the reproductive
processes in the F1 animals, and uncertainty about
the statistical significances. The study has not been peerreviewed.
Utility (Adequacy) for CERHR Evaluation Process:
Although this study was not designed to find non-linear
dose–responses, it represents a conventional-for-the-time
2-generation toxicity study, and is adequate for the
evaluation process but of limited utility because the high
doses preclude evaluation of low dose effects and limit
its utility in showing a lack of marked organ toxicity or
gross reproductive toxicity in a limited number of
animals at very high-doses.
The International Research and Development Corporation
(General Electric, 1978), sponsored by General
Electric, examined the effects of bisphenol A exposure on
male and female CD rats and their offspring. In the first
part of the experiment, male and female rats were
housed in wire mesh cages and were fed Purina
Laboratory Chow containing bisphenol A [purity not
specified] for 18 weeks. Ten rats/group (body weights of
135–179 g for males and 114–158 g for females) were
assigned to each treatment group based on even
distribution of body weight and litter mates. [Based on
information provided in study tables, it appears that
the rats were B30 days old at the start of dosing.]
Bisphenol A was added to feed at concentrations of 0,
100, 250, 500, 750, or 1000 ppm. The European Union
(2003) estimated bisphenol A intake at 0, 5, 15, 30, 50, and
60 mg/kg bw/day in males and 0, 10, 25, 50, 75, and
100 mg/kg bw/day in females. Rats were examined for
clinical signs, body weight gain, and food intake
throughout the study. Estrous cyclicity was examined
in females for 3 weeks before breeding and during
breeding. At 100 days of age (Week 10 of the study), rats
were moved to plastic cages with corncob bedding and
mated for 3 weeks. GD 0 was defined as the day that
vaginal sperm or plug was observed. Rats were assessed
for fertility and gestation length. Day of delivery was
designated lactation day 0 (PND 0). Pups were counted,
sexed, and weighed, assessed for viability at birth and
through the lactation period. After weaning, 15 male and
female F 1 rats/group that were exposed in utero were
selected for a 90-day feeding study. Parental rats and
unselected F 1 rats were killed and discarded.
During a 90-day period, F 1 rats were fed diets
containing the same concentration of bisphenol A as
their parents. [Ages at the start of dosing were not
reported, but based on body weight ranges reported
(64–138 g for males and 57–118 g for females) it appears
that rats were different ages at the start of dosing.] F1
rats were weighed and observed for clinical signs.
Hematological, clinical chemistry, and urinalysis
Birth Defects Research (Part B) 83:157–395, 2008