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

208 CHAPIN ET AL.
60–100% in each dose group with the exception of
females exposed to 250 ppm was considered to be
treatment-related. No histological alterations were observed
in the cecum. Death in mice was limited to 2 of 10
females in the 5000 ppm group. Weight gain was reduced
by at least 14% in male mice exposed to Z15,000 ppm.
Non-dose-related decreases in weight gain of 17% or
more occurred in female mice of all dose groups. A doserelated
increase in multinucleated giant hepatocytes was
observed in all dose groups of male mice; the only
incidence data reported for multinucleated giant hepatocytes
were 0 of 10 female controls and 9 of 10 male mice
of the 25,000 ppm group. [A complete set of data for
histopathological findings was not presented for rats or
mice.]
Yamasaki et al. (2002a) examined the effects of
bisphenol A exposure on male and female CD rats in a
study conducted according to Good Laboratory Practices
(GLP). [Because this study included a number of
reproductive organ and hormone endpoints, it is also
discussed in Sections 4.2.1.1 and 4.2.2.1.] Rats were fed a
commercial diet (MF Oriental Yeast Co.) and housed in
stainless steel wire-mesh cages. Rats were groups
according to body weight and then randomly assigned
to treatment groups. Ten 7-week-old rats/sex/group
were gavaged with bisphenol A at 0 (olive oil vehicle),
40, 200, or 1000 mg/kg bw/day for 28 days. Due to the
death of 1 animal exhibiting clinical signs in the
1000 mg/kg bw/day group, the high-dose was reduced
to 600 mg/kg bw/day on Study Day 8. In an additional
study, rats were exposed to ethinyl estradiol at 0, 10, 50,
or 200 mg/kg bw/day for 28 days. Endpoints examined
during the study were clinical signs, body weight gain,
and food intake. Estrous cyclicity was examined in
females for 2 weeks beginning on Study Day 15. Males
were killed on Study Day 29 and females were killed in
diestrus on Study Day 30, 31, or 32. Hematology and
clinical chemistry endpoints were assessed, and blood
hormone concentrations were measured by immunoassay
systems. Sperm motility and viability were evaluated.
Organs, including those of the reproductive system,
were weighed and subjected to histopathological evaluation.
With the exception of the testis and epididymis,
which were fixed in Bouin solution, the organs were
fixed in 10% neutral buffered formalin. Statistical
analyses included Bartlett test for homogeneity of
variance, ANOVA, Dunnett test, and/or Kruskall–Wallis
test.
One female and 3 males from the high-dose group
died; clinical signs observed in those animals included
soft stools, decreased mobility, reduced respiration rate,
and decreased body temperature. Soft stools were also
observed in surviving males and females of the mid- and
high-dose groups. Results of the study are summarized
in Table 51. Terminal body weights were lower in females
of the mid- and high-dose groups and males of the highdose
group. During the first week of study, food intake
was decreased in both sexes of the mid- and high-dose
group. [Data were not shown by study authors.] As
noted in Table 51, some alterations in hematological and
clinical chemistry endpoints were observed, mainly at
the high-dose. [Data were not shown by study authors.]
There were no treatment-related abnormalities in sperm
or alterations in blood concentrations of thyroid hormones,
follicle stimulating hormone (FSH), luteinizing
Table 51
Toxicological Effects in Rats Gavaged With Bisphenol A
for 28 Days a
Endpoint
Males
Terminal body weight
Relative testes weight
Relative ventral prostate
weight
Relative adrenal weight
Feed intake b
Prothrombin time b
Glutamic-oxaloacetic
transaminase b
Triglyceride b
Alkaline phosphatase b
g-Glutamyl transpeptidase b
Chloride b
Renal tubular degeneration
and necrosis
Forestomach squamous
epithelial cell hyperplasia
Lacteal dilatation in
duodenum
Lacteal dilation in jejunum
Mucosal hyperplasia in cecum
Mucosal hyperplasia in colon
Adrenal cortical vacuolization
Females
Terminal body weight
Relative thyroid weight
Relative liver weight
Relative heart weight
Feed intake b
Hemoglobin and
hematocrit values b
Cholinesterase b
Glutamic-oxaloacetic
transaminase b
Albumin and albumin:
globulin rats b
Diestrus Z4 days
Prominent hepatocyte nuclei
Renal tubular degeneration
and necrosis
Forestomach squamous
epithelial cell hyperplasia
Lacteal dilatation in duodenum
Mucosal hyperplasia in cecum
Adrenal cortical vacuolization
Bisphenol A dose
(mg/kg bw/day)
40 200 600–1000 c
2 2
2 2
2 2
2 2
2 k
2 2
2 m
2 2
2 2
2 2
2 2
0/10 0/10
0/10 0/10
0/10 10/10
0/10 0/10
0/10 3/10
0/10 2/10
0/10 0/10
2 k 7%
2 2
2 2
2 k 9%
2 k
2 2
2 k
2 2
2 2
0/10 0/10
0/10 0/10
0/10 0/10
0/10 0/10
0/10 7/10
0/10 6/10
0/10 0/10
k 17%
m 21%
k 28%
m 19%
k
m
m
k
m
m
m
7/7
6/7
2/7
2/7
6/7
7/7
3/7
k 5%
m 22%
m 10%
k 15%
k
k
a Yamasaki et al. (2002a).
b Data were not shown by study authors.
c The dose was 1000 mg/kg bw/day at the beginning of the
study, but was decreased to 600 mg/kg bw/day in the second
week of the study due to excessive toxicity.
m,k Statistically significant increase, decrease compared to
controls; 2 no statistically significant effects compared to
controls.
hormone (LH), 17b-estradiol, prolactin, or testosterone.
Number of females with diestrus lasting 4 or more days
was increased in the high-dose group. Changes in
relative organ weights [assumed to be relative to body
k
m
k
3/9
4/9
9/9
5/9
6/9
4/9
3/9
Birth Defects Research (Part B) 83:157–395, 2008