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

weight] included decreased heart weight in females from
the mid- and high-dose groups. At the high-dose, there
were decreases in relative weight of ventral prostate and
increases in relative weights of testis and adrenals in
males and thyroid and liver in females. Gross signs
observed in animals that died included enlarged kidney,
elevated mucosa in the forestomach, and atrophied
spleen and thymus. In surviving animals, the cecum
was enlarged in the mid- and high-dose group and
forestomach mucosa was elevated in the high-dose
group. As described in more detail in Table 51, histopathological
alterations were observed in the intestine,
cecum, and colon of males and intestine and cecum of
females in the mid- and high-dose groups. Additional
histopathological alterations were observed in the highdose
group in the kidney, forestomach, and adrenals of
males and females and livers of females.
Male rats from the mid- and high-dose ethinyl
estradiol groups experienced decreased prostate, seminal
vesicle, and pituitary weights, increased testis weight,
and histopathological alterations in prostate, seminal
vesicle, mammary gland, and testis. Females from the
mid- and high-dose ethinyl estradiol group experienced
alterations in estrous cyclicity. Females from the
high-dose group experienced decreased ovary weight,
increased uterine weight, and histopathological changes
in ovary, uterus, and vagina.
General Electric (1984) conducted a subchronic toxicity
study in Beagle dogs orally dosed with bisphenol A
[purity not reported]. Dogs weighing 6.5–13.4 kg were
housed in metal metabolism cages and fed Purina Dog
Chow. During a 90-day period, 4 dogs/sex/group were
given feed containing bisphenol A at 0, 1000, 3000, or
9000 ppm. The European Union (2003) estimated bisphenol
A intake at 0, 28, 74, or 261 mg/kg bw/day in
males and 0, 31, 87, or 286 mg/kg bw/day in females.
Dogs were observed for body weight gain, food, intake,
and clinical signs. Ophthalmoscopic examination was
conducted before and following the treatment period.
Hematology, clinical chemistry, and urinalysis evaluations
were conducted before treatment and at 1, 2, and 3
months into the study. Dogs were killed at the end of the
treatment period. Organs were weighed and fixed in 10%
neutral buffered formalin. Histopathological evaluations
were conducted in organs from the control and high-dose
groups; prostate, uterus, testis, and ovary were among
organs evaluated. [Procedures for statistical analyses
were not described.] No treatment-related clinical signs
(conducted monthly), ophthalmological changes, or
death were observed during the study. Bisphenol A
treatment did not affect body weight gain or food intake.
There were no treatment-related effects on hematology,
biochemistry, or urinalysis. Relative liver weight was
significantly increased [by 18% in males and 26% in
females] in the high-dose group, and the study authors
considered the effect to be treatment-related. No treatment-related
gross or histopathological lesions were
observed in the high-dose group.
Nitschke et al. (1988) conducted a subchronic inhalation
toxicity test with bisphenol A in F344 rats. Rats were
fed Purina Certified Rodent Chow 5002 and housed in
stainless steel wire cages. At 7 weeks of age, rats were
stratified according to body weight and randomly
assigned to treatment groups. Thirty rats/sex/group
received whole-body exposures to polycarbonate grade
Birth Defects Research (Part B) 83:157–395, 2008
BISPHENOL A
209
bisphenol A dust (99.7% purity) at 0, 10, 50, or 150 mg/
m 3 for 6 hr/day, 5 days/week, for 13 weeks. Mass
median aerodynamic diameter of bisphenol A dust was
measured at r5.2 microns. Stability and concentrations
of bisphenol A were verified. Rats were observed for
clinical signs, body weight gain, and food intake. Ten
rats/sex/group in each time period were killed and
necropsied on the day following and at 4 and 12 weeks
following exposure. At each necropsy period, hematological
and clinical chemistry endpoints were examined.
The lungs, brain, kidneys, and testes were weighed.
Numerous organs were preserved in 10% phosphatebuffered
formalin. In most cases, histological examinations
were conducted in organs from the control and
high-dose groups. Respiratory organs and organs with
lesions or signs of toxicity were histologically examined
at all dose levels. Included among organs undergoing
histopathological examination immediately after the
exposure period were the epididymis, mammary gland,
ovary, oviduct, prostate, seminal vesicles, testis, uterus,
and vagina. No reproductive organs were examined
following the recovery periods. Statistical analyses
included Bartlett’s test, ANOVA, Dunnett test, Wilcoxon
Rank-Sum test, and Bonferroni correction for multiple
comparisons. Gross pathology and histopathology data
did not appear to have been statistically analyzed.
During the exposure period, a reddish material around
the nose (most likely porphyrin) was observed in 2–10 of
10 animals/sex in the 50 and 150 mg/m 3 groups. Perineal
soiling was observed in 2 of 10 females in the 10 mg/m 3
group and 9–10 of 10 animals/sex in the 50 and 150 mg/
m 3 groups. Decreased body weight gain during treatment
was observed in males from all dose groups and
females in the 50 and 150 mg/m 3 groups. Immediately
following the treatment period, terminal body weights
were reduced by B5% in males and B11% in females
from the 150 mg/m 3 group. [Body weights were B4%
lower in males from the 50 mg/m 3 group.] No differences
in feed intake were observed at this or any other
time period in the study. The only hematological effect
observed was slightly increased hemoglobin in males
exposed to 10 mg/m 3 , but the study authors did not
consider the effect to be biologically significant. Clinical
chemistry observations in the 150 mg/m 3 group included
decreased serum glutamic pyruvic transaminase activity,
serum glutamic oxaloacetic transaminase activity, and
glucose in males and decreased total protein and
albumin and increased alkaline phosphatase activity in
females. Alkaline phosphatase activity was also increased
in females exposed to 50 mg/m 3 . The study
authors did not consider any of the clinical chemistry
changes to be biologically [toxicologically] significant.
Absolute liver weight was decreased in males exposed to
Z10 and 150 mg/m 3 , and relative brain weight was
increased in females exposed to Z50 mg/m 3 . Additional
organ weight changes observed in females from the
150 mg/m 3 group included decreased absolute liver and
kidney weights and increased relative lung weights.
Because the organ weight changes were not associated
with microscopic changes in organs, the study authors
concluded that the effects reflected decreases in body
weight and were not toxicologically significant. Cecal
size was increased as a result of distention by food in all
(10/dose/sex) males and females exposed to Z50 mg/
m 3 , and the effect was considered to be treatment-