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

The European Union (2003) noted limited anecdotal
data reporting skin, eye, and respiratory tract irritation in
workers exposed to bisphenol A, but concluded that the
reports were of uncertain reliability. It was noted that a
recent, well-conducted study in rabbits demonstrated
that bisphenol A is not a skin irritant. Other studies
conducted in rabbits demonstrated eye irritation and
damage, and it was concluded the bisphenol A can
potentially cause serious eye damage. Slight respiratory
tract inflammation occurred in rats inhaling Z50 mg/m 3
bisphenol A, and it was concluded that bisphenol A had
limited potential for respiratory irritation. Based on the
results of the studies described above, the European
Union concluded that bisphenol A is not corrosive.
The European Union (2003) reviewed studies examining
possible sensitization reactions in humans exposed to
products containing bisphenol A, and those studies
reported mixed results. In studies reporting positive
findings, it was unclear if bisphenol A or epoxy resins
were the cause of hypersensitivity. Cross-sensitization
responses in individuals exposed to compounds similar
to bisphenol A were also reported. Animal studies were
determined unreliable for assessing sensitization. Based
on the results of human studies, it was concluded that
bisphenol A may have potential for sensitization in
individuals exposed to resins. Human studies suggested
that bisphenol A can induce dermal photosensitization
responses. Photosensitization studies in mice resulted in
reproducible positive results. Mechanistic studies in mice
suggested that sensitization occurs through an immunemediated
process. The overall conclusion of the European
Union was that it was somewhat unclear if
bisphenol A induces orthodox skin sensitization, photosensitization,
or responses in individuals previously
sensitized to another substance, such as epoxy resins.
No information was available on potential respiratory
sensitization by bisphenol A.
The European Union (2003) summarized systemic
toxicity reported in subchronic, chronic, and reproductive
toxicity studies of rats, mice, and dogs. CERHR also
reviewed the studies that examined reproductive organs,
and those studies are summarized in detail in the
appropriate section of this report. A relevant study by
Yamasaki et al. (2002a) was published subsequent to the
European Union review and was reviewed in detail by
CERHR.
In studies reviewed by the European Union (2003) and
in a study by Yamasaki et al. (2002a), rats were orally
exposed to bisphenol A for periods of 28 days to 2 years.
Cecal enlargement occurring at doses Z25 mg/kg bw/
day was the effect observed most frequently in those
studies but was not considered toxicologically significant
by the European Union. Histological alteration in the
cecum consisting of mucosal hyperplasia was only
reported in one study at doses Z200 mg/kg bw/day.
Histopathological changes in liver and kidney were
reported at doses Z500 mg/kg bw/day. The changes in
liver were characterized by prominent hepatocyte nuclei
or inflammation. Histopathology in kidney was characterized
by renal tubule degeneration or necrosis.
Testicular toxicity (degeneration of seminiferous tubules
and arrested spermatogenesis) was observed in 1 study
at doses Z235 mg/kg bw/day.
The European Union (2003) found subchronic and
chronic studies conducted by the NTP (NTP, 1982) to be
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theonlyreliablestudies forassessing systemic toxicity in
mice orally exposed to bisphenol A. The liver was found to
be the target organ of toxicity, with multinucleated giant
hepatocytes observed in male mice exposed to Z120 mg/kg
bw/day and female mice exposed to 650 mg/kg bw/day.
In a 90-day dietary study in dogs reviewed by the
European Union (2003), an increase in relative liver weight
with no accompanying histopathological alterations was
found to be the only effect at doses Z270 mg/kg bw/day.
This finding was considered by the European Union to be
of doubtful toxicological significance.
In a subchronic inhalation exposure study in rats
reviewed by the European Union (2003), cecal enlargement
as a result of distention by food was observed at
Z50 mg/m 3 . Also observed at Z50 mg/m 3 were slight
hyperplasia and inflammation of epithelium in the
anterior nasal cavity.
A limited number of repeat-dose systemic toxicity
studies were summarized in detail by CERHR because
they included examination of reproductive organs. Those
studies are summarized in detail below.
NTP (1982), conducted acute, subacute, and subchronic
bisphenol A toxicity studies in F344 rats and B6C3F1
mice. Animals were randomly assigned to treatment
groups. Purity of bisphenol A was o98.2%. Concentration
and stability of bisphenol A in feed were verified. In
acute studies, single doses of bisphenol A in a 1.5%
acacia vehicle were administered by gavage to 5 rats/
group/sex at doses of 2150, 3160, 4640, or 6810 mg/kg
bw/day and 5 mice/group/sex at 1470, 2150, 3160, 4640,
6810, or 10,000 mg/kg bw. LD50 values for that study are
summarized in Table 50.
In a 14-day repeat dose study, survival and body
weight gain were evaluated in 5 rats and mice/sex/
group that were fed diets containing bisphenol A at 0,
500, 1000, 2500, 5000, or 10,000 ppm. Survival was
unaffected by treatment. Weight gain was reduced by
60% or more in male rats exposed to Z2500 ppm and
40% or more in female rats exposed to Z5000 ppm
bisphenol A. Survival and weight gain in mice were not
affected by bisphenol A exposure.
In subchronic studies, 10 rats and mice/sex/group
were exposed to bisphenol A in diet for 13 weeks.
Dietary doses were 0, 250, 500, 1000, 2000, or 4000 ppm
for rats and 0, 5000, 10,000, 15,000, 20,000, or 25,000 ppm
for mice. A review by the European Union (2003)
estimated bisphenol A intake at 0, 25, 50, 100, 200, and
400 mg/kg bw/day for rats, 0, 600, 1200, 1800, 2400, and
3000 mg/kg bw in male mice, and 0, 650, 1300, 1950,
2600, and 3250 mg/kg bw/day in female mice. Animals
were observed and weighed during the study and killed
and necropsied on Day 91 of the study. [Histopathological
evaluations were conducted but it was not clear if
all dose groups and all animals/dose group were
examined. There was no mention of statistical analyses.]
In rats, the only deaths occurred in 2/10 males of
the 1000 ppm group. Weight gain was reduced by 18% or
more in male rats and 10% or more in female rats
exposed to Z1000 ppm. There were no effects on feed
intake. Hyaline masses in the bladder lumen were not
observed in control male rats but were observed in 5 of
10 males exposed to 250 ppm, 3 of 10 exposed to
500 ppm, 3 of 10 exposed to 1000 ppm, 6 of 10 exposed
to 2000 ppm, and 4 of 10 exposed to 4000 ppm. Cecal
enlargement, which was observed in rats at a rate of