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EC number: 201-245-8
CAS number: 80-05-7
Bisphenol A; BPA
After oral administration, Bisphenol A is rapidly metabolised by intestinal tissue and the liver to Bisphenol A glucuronide. In humans, the glucuronide is released from the liver into the systemic circulation and cleared rapidly by urinary excretion. In contrast, Bisphenol A glucuronide is primarily eliminated in bile in rodents with some partial urinary excretion. The Bisphenol A glucuronide excreted via the bile in rodents undergoes enterohepatic recirculation after cleavage to Bisphenol A and glucuronic acid by glucuronidase in the intestinal tract.
Criteria for IUCLID chapter 7 dossier preparation applied in the initial
dossier 2010 and the update 2015:
Initial dossier submitted in 2010:
Due to the large data set on Bisphenol A, criteria were established to
define Key-Studies, Supporting-Studies and additional studies to cover
all available data for the human health hazard assessment. In the
original dossier submitted in 2010 the human health hazard assessment
was based on the initial EU Risk Assessment Report 2003 on Bisphenol A
and the EU Risk Assessment Update in 2008. For each endpoint the
conclusion of the EU Risk Assessments in 2003 and 2008 are cited and, if
available, additional relevant information not evaluated in one of the
Risk Assessments is indicated. Key studies were defined as comprehensive
studies conducted according to scientifically accepted methods and
performed according to or exceeding validated guidelines (e.g. OECD
testing guidelines). Supporting studies were defined as comprehensive
studies conducted to scientifically accepted methods and performed
similar to validated guidelines with only very minor deviations.
Additional exploratory studies were cited in chapters 7.9.3.” specific
investigations: other studies” and 7.12. “additional toxicological
Dossier update in 2015:
The summaries and conclusions of the initial dossier are included in the
endpoint summaries of the update.
A literature search is performed to cover literature between the initial
dossier submission (July 2009) and July 2015. As in the initial dossier
key studies are defined as comprehensive studies conducted according to
scientifically accepted methods and performed according to or exceeding
validated guidelines (e.g. OECD testing guidelines). Supporting studies
are defined as comprehensive studies conducted to scientifically
accepted methods and performed similar to validated guidelines with only
very minor deviations. Starting in 2008 and continuing through 2015,
researchers at several US federal government laboratories (EPA, FDA,
National Toxicology Program, CDC, Pacific Northwest National Laboratory)
have been conducting in-depth research to answer key scientific
questions and resolve uncertainties about the safety of Bisphenol A.
These studies e.g. are included in the updated dossier with robust study
Recently SCOEL recommendation (2014) and EFSA opinion (2015) became
available and for each endpoint their conclusion is cited.
Additional exploratory studies identified during the updated literature
search are also cited in chapters 7.9.3.” specific investigations: other
studies” and 7.12. “additional toxicological information”.
Discussion on toxicokinetics:
The 2003 EU RAR concluded:
"Animal data indicates that absorption of Bisphenol A from the
gastrointestinal tract is rapid and extensive following oral
administration, although it is not possible to reliably quantify the
extent of absorption. Following dermal exposure, available data suggest
limited absorption of about 10% of the applied dose. Bisphenol A is
removed rapidly from the blood and the data indicate extensive first
pass metabolism following absorption from the gastrointestinal tract. In
view of this first pass metabolism, the bioavailability of unconjugated
Bisphenol A is probably limited following oral exposure to no more than
10 to 20% of the administered dose. The major metabolic pathway in rats
involves glucuronide conjugation, with approximately 10% and 20% of the
administered dose recovered in urine as the glucuronide metabolite in
males and females, respectively. The major route of excretion is via the
faeces with the urinary route being of secondary importance. Over seven
days post dosing, approximately 80% and 70% of the administered dose was
eliminated in the faeces in male and female rats, respectively. The
first pass metabolism and extensive and rapid elimination of Bisphenol A
suggest that the potential for transfer to the foetus and
bioaccumulation may be limited. There are no data on the toxicokinetics
of Bisphenol A following inhalation exposure."
The 2008 updated EU RAR concluded:
"New information on the toxicokinetics of Bisphenol A in humans
and in pregnant and non-pregnant rodents of different ages provides an
important contribution to the knowledge of kinetic properties of
Bisphenol A. Human studies have demonstrated that at comparable exposure
levels the blood concentrations of free Bisphenol A in humans are much
lower than those in rodents. In rats, mice, monkeys, and humans, the
available evidence suggests that following oral administration,
Bisphenol A is rapidly and extensively absorbed from the
gastrointestinal tract. For the purposes of risk characterisation,
absorption via the oral and inhalation routes will be assumed to be
100%; dermal absorption will be taken to be 10%. A number of studies in
rats suggest that Bisphenol A metabolites and free Bisphenol A have a
limited distribution to the embryo/foetal or placental compartments
following oral administration. Maternal and embryo/foetal exposure to
free Bisphenol A did occur, but systemic levels were found to be low due
to extensive first-pass metabolism. There are differences between humans
and rodents in the distribution of Bisphenol A. After oral
administration, Bisphenol A is rapidly metabolised in the gut wall and
the liver to Bisphenol A glucuronide. In humans, the glucuronide is
released from the liver into the systemic circulation and cleared by
urinary excretion. In contrast, Bisphenol A glucuronide is eliminated in
bile in rodents and undergoes enterohepatic recirculation after cleavage
to Bisphenol A and glucuronic acid by glucuronidase in the intestinal
Additional relevant information since 2010 taken into account for the
EFSA 2015 Conclusions on toxicokinetics:
"The kinetic data available indicate species- and life
stage-dependent differences. Such variability has to be considered when
data of different species are compared. Conjugation to Bisphenol
A-glucuronide, which is a biologically inactive form, is the major
metabolic pathway of Bisphenol A in humans and animals. A study in
humans on high Bisphenol A diets (Teeguarden et al., 2011) showed that
unconjugated Bisphenol A in serum was below the LOD of 0.3 ng/ml (= 1.3
nM), confirming under the condition of the study that internal exposure
to unconjugated Bisphenol A is low. The percentage of unconjugated
Bisphenol A in blood is only a few percent of total Bisphenol A (sum of
conjugated and unconjugated Bisphenol A). Based on the analysis of oral
(gavage) versus intravenous toxicokinetic data, the oral systemic
bioavailability of unconjugated Bisphenol A in rats is 2.8 %, in mice
0.45 % and in monkeys 0.9 % (Doerge et al., 2010a,b, 2011a, b, 2012).
The concentrations measured in the animal studies and also in the human
study render the relevance of serum or blood concentrations in humans,
which were measured and reported by some authors in the literature (see
Section 4.6.3 in Part I – Exposure assessment) as rather unplausible.
Experimental data on the systemic availability of unconjugated Bisphenol
A in humans has until now not been published. From studies on
physiologically based pharmacokinetic (PBPK) modelling it can be
concluded, that at relevant oral exposures (e.g. < 1 μg/kg bw per day)
the maximum serum concentrations (Cmax) of unconjugated Bisphenol A are
in the 3.2–160 pg/ml (7–37 pM) range, depending on the model used
(Mielke and Gundert-Remy, 2009; Edginton and Ritter, 2009; Fisher et
al., 2011; Yang et al., 2013). Bisphenol A does not accumulate in the
body even though the concentration of unconjugated Bisphenol A is
somewhat higher in fat compared to serum.
Some new animal data in particular in mice, rats and monkey give more
insight into the kinetics of Bisphenol A, in particular into the
age-dependent maturation of conjugation reactions. Also, diaplacentar
transfer of Bisphenol A has been measured in rat and monkey. Data in
rats indicate that in early pregnancy transfer to the fetus might be
greater compared to later pregnancy after IV injection exposure of
Bisphenol A (fetus/dam concentration ratios: 2.8 at GD 12, 1.2 at GD 16,
0.4 at GD 20). Unconjugated Bisphenol A and Bisphenol A-conjugates are
measured in the amniotic fluid of rats and rhesus monkeys at low
concentrations. Bisphenol A is found in milk of rat dams exposed to
Bisphenol A at a level of 100 ug/kg bw per day in the unconjugated and
conjugated forms. The amount delivered to the pups is so small that the
concentrations in pup serum are below 0.2 nM (45.6 pg/ml), and therefore
pup exposure via lactation is extremely low (1/300 of the maternal
dose). These data are in marked contrast to the average concentrations
reported for human breast milk (unconjugated Bisphenol A 0.3 ng/ml;
total Bisphenol A 1.1 ng/ml )despite the fact that the average human
exposure is 1/1000 of the rat exposure exposure (see Chapter 4.6.4. in
Part I – Exposure assessment).
Polymorphisms have been described for the enzymes relevant for the
conjugation of Bisphenol A. Since Bisphenol A conjugation can be carried
out by several enzymes, a single polymorphism in one gene, resulting in
a reduction or loss of enzymatic activity of functional enzymes may
result in a change in the plasma levels of unconjugated Bisphenol A.
Since Bisphenol A is glucuronidated by two UTGs and is conjugated not
only to glucuronides but also to sulphates, it can be assumed that the
increase in blood concentration is modest. This assumption has been
confirmed also in the PBPK modelling study by Partosch et al. (2013)
showing a 4-fold difference in AUC and Cmax between the human PBPK
models with the highest and the lowest metabolic activity. This
difference in sensitivity of Bisphenol A in the human population is
covered by the assessment factors used in the risk assessment of
A solid base of toxicokinetic studies in various laboratory animal
species (Doerge et al., 2010a,b,c; 2011a,b; 2012) provide internal dose
metrics for neonatal-to-adult stages and for different routes of
exposure (oral and intravenous/subcutaneous). Moreover, PBPK models have
been developed to predict the internal exposures in laboratory animals
and humans in a route-specific manner. Overall, this body of information
permits extrapolation to humans and the application of the HED concept
for providing HEDF which account for the toxicokinetic portion of the
interspecies differences. Multiplying the HEDF by a reference point of a
critical toxicity study yields a human-equivalent oral dose that is used
for risk assessment. The assessment of the physiological plausibility of
the derived HEDF values for adult animals with oral dosing revealed a
good agreement of the HEDF for monkeys with the allometric
scaling-derived DAF. In rats, the HEDF was 3-times higher than the DAF
which can be explained by the effect of enterohepatic recirculation,
serving to extent the exposure to Bisphenol A. For mice, the HEDF was
2-times lower than the DAF, which suggests a greater metabolic capacity,
serving to reduce the AUC. The Panel noted that due to limitations in
the analytical detectability of unconjugated Bisphenol A in mouse serum,
the HEDF for mice may be conservative by a factor of 5.
The available evidence from in vitro skin absorption experiments with
human, pig and rat skin and from in vivo studies on dermal absorption in
rats suggests a 24-h dermal absorption for human skin of 2.3–8.6%. For
exposure scenarios with dermal contact to thermal paper, the CEF Panel
decided to use a skin penetration of 10%. The CEF Panel decided not to
consider the amount deposited in the stratum corneum as becoming
available for systemic uptake for reasons emerging from the PBPK
modelling of dermal exposure. The CEF Panel further decided not to
consider skin metabolism in dermal exposure scenarios as the available
information does not permit to arrive at a reliable estimate of the
extent of skin metabolism. Not to consider skin metabolism is a
conservative decision. The CEF Panel noted that the assumption of 10%
dermal absorption for the hand contact to thermal paper is also a
further conservative decision, since the absorption across the skin of
the palms can be expected to be lower than in other body parts because
of the thicker stratum corneum. For scenarios with aggregated oral and
dermal exposures, PBPK modelling was used to estimate the internal dose
metrics for unconjugated Bisphenol A and to convert external dermal
doses into an equivalent oral doses."
requested an in vitro dermal penetration study to be conducted by the
registrant. As requested by ECHA this study was performed in accordance
with Good Laboratory Practice regulations (Toner 2015). This
study was also performed in accordance with the following guidelines:
OECD Guideline for Testing of Chemicals, Guideline 428: Skin Absorption:In
OECD Environmental Health and Safety Publications Series on Testing and
Assessment No. 28. Guidance
Document for the Conduct of Skin Absorption Studies (2004).
Scientific Committee on Consumer Safety (SCCS). Basic Criteria for theIn
VitroAssessment of Dermal Absorption of Cosmetic Ingredients. SCCS/1358/10,
22 June 2010.
indicated that there are a number of points that require special
attention that shall be considered:
design of the diffusion cell (technicalities and choice between static
and flow through system).
automated flow-through diffusion cell apparatus was used. Continuous
sampling is the advantage of a flow-through system compared to a static
fluid was collected at regular intervals between 0.5 and 24 h. The
selected laboratory has extensive experience with flow-through diffusion
choice of the receptor fluid (physiological pH, solubility and stability
of chemical in receptor fluid should be demonstrated, no interference
with skin/membrane integrity, analytical method, etc.):
receptor fluid was a tissue culture medium (Dulbecco's Modified Eagle
Medium; DMEM) containing ethanol (ca1%, v/v), Uridine
5’‑diphosphoglucuronic acid (UDPGA, 2 mM) and
3’-phosphoadenosine-5’-phosphosulfate (PAPS, 40 µM).
was selected since the laboratory has experience with this medium as
receptor fluid and it does not interfere with the skin/membrane
integrity (see below).
support UGT and SULT metabolism the cofactorsUridine
acid (UDPGA; 2 mM) and 3’-phosphoadenosin-5’-phosphosulfate (PAPS;0
µM)) were added.
separate solubility experiment demonstrated that the applied dose of
Bisphenol A in in the high concentration (300 mg/l) could potentially be
collected within the first hour of receptor fluid collection of the 24 h
monitoring period. Therefore,
this receptor fluid was not rate limiting for solubility and was
acceptable for use on this study.
of Bisphenol A and Bisphenol A-glucuronide in receptor fluid was
demonstrated over the whole incubation time (24h).
integrity is of key importance and should be verified.
integrity was demonstrated by electrical resistance at the beginning of
the experiment and at the end of the experiment (24h).
temperature has to be ascertained at normal human skin temperature.
flow-through diffusion cells were placed in a manifold heatedviaa
circulating water bath set to maintain a skin surface temperature at 32
°C ± 1 °C.
test substance has to be rigorously characterized.
labelled Bisphenol A ([ring14C(U)]-Bisphenol) was
supplied by Moravek Biochemicals Inc, 577 Mercury Lane, Brea, California
92821, USA. The
Certificate of Analysis stated that the specific activity and
radiochemical purity were 474 µCi/mg and 99.8%, respectively.
Bisphenol A was supplied by Sigma-Aldrich, 3050 Spruce Street, Saint
Louis, MO 63103, USA. A
copy of the Certificate of Analysis is provided in Appendix 3. The
Certificate of Analysis stated chemical purity of 99.9%.
certified metabolite reference standards (Bisphenol A glucuronide sodium
salt and Bisphenol A sulfate sodium salt were available.
(several small dosages shall be used) and vehicle (aqueous
solution)/formulation should be representative for the in-use conditions;
buffered saline (PBS) was used as a vehicle. Initially the use of
artificial sweat was considered but there are >40 formulations reported
in the literature (e.g. Stefaniak et al. Toxicology in vitro 2006,
20:1265-83) with different complexity (Harvey et al. 2010,24:1790-96)
and no rational when to use individual formulations. In
addition no information was available if any of these formulations
interfere with the skin/membrane integrity, viability of the fresh skin
used or potential metabolic activity of UGTs and/or SULTs.
low dose, 2 mg/l, was
selected to give ca. 2000 dpm radioactivity (limit of quantification) as
a measure for absorption. (Skin surface area (cm2): 0.64; Application
rate of Formulation (µL/cm2): 10 (standard according to guideline;
higher values have to be justified); Specific activity Bisphenol A: 474
µCi/mg; Assumption concerning absorption: 10% of applied dose will be
high dose was selected at the solubility limit of 300 mg/l. This
concentration will lead to a surface dose of 1,92 µg/0.64 cm2=
3 µg/cm2, which is in same order as Biedermann et al
(Anal. Bioanal. Chem. 2010. 398: 571-576) reported in a worst-case
assumption on exposure via thermo paper (4-16 µg/cm2).
dose level between the high and low-dose is covered by 2 interim doses
spaced by a constant factor of 5.
the following concentrations were selected for the main study: 300, 60,
12, 2.4 mg/l
volume and contact time with the skin have to mimic in-use conditions.
The duration has to be at least 24 hours. For measurements and
calculation of the percentage of absorption the low end of the
anticipated exposure should be tested.
measuring the metabolism also the highest exposure should be included;
the study shall investigate metabolites of Bisphenol A in the relevant
compartments of the skin since at least the Zalko study gave evidence
for a significant formation of Bisphenol A metabolites in the skin.
rates were relative constant over the dose levels investigated.
skin was used since a pilot experiment verified that Bisphenol A-G and
Bisphenol A-S is observed after incubation of fresh skin and by that
confirmed some metabolic capability of the skin under the above
sampling is required over the whole exposure period;
of Bisphenol A was assessed by collecting fractions of receptor fluid at
0, 0.5, 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24 h post dose.
analytical techniques should be used. Their validity, sensitivity and
detection limits should be documented in the report;
analysis was conducted and the sensitivity and detection limits are
test compound is to be determined in all relevant compartments:
product excess on the skin surface (dislodgeable dose),
stratum corneum (e.g.adhesive
living epidermis (without stratum corneum),
on all mentioned compartments are reported.
balance analysis and recovery data are to be provided. The overall
recovery of test substance (including metabolites) should be within the
range of 85-115%; and
balance is reported and within the given range.
skin samples from at least 4 donors shall be used. Variability /
validity / reproducibility of the method shall be demonstrated and
human skin samples from 4 donors were investigated. Each
donor was run in triplicate (each donor contains 3 skin disks for
absorption). Overall, 12 skin samples were were used for each dose level.
amount measured in the dermis, epidermis (with stratum corneum) and
receptor fluid will be considered as dermally absorbed and taken into
account for further calculations.
followingdermal absorption rates were reported in this
Target Concentration (mg/L)
(% Applied Dose)
Total Dislodgeable Dose
Total Unabsorbed Dose
Total Absorbed Dose
are two guidance documents to calculate the potential dermal absorption
based on in vitro data.
EFSA Guidance on Dermal Absorption (EFSA Journal 2012. 10,
receptor fluid + receptor chamber washes + skin sample (excluding tape
strips 1 and 2). The guidance indicates:“There
is a general practise within EFSA PRAPeR9 meetings that the first 2 tape
strips will represent material that will not become bioavailable due to
desquamation. The Panel proposes to follow this approach. Thus, the
first 2 tape strips can be excluded when calculating dermal absorption
…If there is significant variation between replicates (i.e. the standard
deviation is equal to or larger than 25% of the mean of the absorption
as defined in section 5.6. and 5.8.) consideration should be given to
using a value other than the mean or rejecting the study entirely. The
preferred approach would be the addition of a standard deviation to the
mean value. that the application site was swabbed to remove the test
material before termination of the study.”
the EFSA guidance leads to the following potential absorption values;bold
values denote value to be used according to the EFSA Guidance.
Basic Criteria for the in vitro assessment of dermal absorption of
cosmetic ingredients (SCCS/1358/1)
defines absorption as follows:“In a classicalin
absorption setting, the amounts of penetrated substance(s) found in the
receptor fluid are considered to be systemically available.Both the
epidermis (except for the stratum corneum) and dermis are considered as
a sink, wherefore the amounts found in these tissues are considered as
absorbed and are added to those found in the receptor fluid.The
amounts that are retained by the stratum corneum at the time of sampling
are not considered to be dermally absorbed, and thus they are not
expected to contribute to the systemic dose.
studies correspond to all of the basic requirements of the SCCS, themean
+ 1SDwill be used for the calculation of the MoS… In case of
significant deviations from the protocol and/or very high variability,
themean + 2SDwill be used as dermal absorption for the
calculation of the margin of safety.”
the EFSA guidance leads to the following potential absorption values;no
clear guidance is given on guideline to define if 1 or 2 SD should be
a potentially bioavailable portion of Bisphenol A of 30% is taken to
derive a corrected dermal starting point for DNEL derivation.
metabolism was also investigated in this study. No metabolism was
observed in any of the epidermis samples, however limited levels of
metabolism were observed in dermis and receptor fluid samples (0-14%)
with formation of Bisphenol A-glucuronide and Bisphenol A-sulfate
identified in supernatant from incubation of viable skin disks for 24 h
with retention consistent with Bisphenol A-glucuronide and Bisphenol
A-sulfate, and also more polar components, were identified. It might be
assumed, but is not analytically verified, that these polar compounds
are mixed sulfate/glucuronide bis-conjugate Bisphenol A metabolites. It
can be concluded qualitatively that fresh human skin has somein vitrometabolic
capacity but further experiments may be necessary to optimize the
experimental conditions to quantify that metabolism.
as a conservative approach no metabolism was taken into account.
with available in vitro data:
(2015) summarized the available data as follows“In
Demierre et al. (2012), the specific permeation kinetics with an initial
high penetration rate and a subsequent low penetration rate are
suggestive of effects arising from finite dosing (i.e. partial depletion
of the dose on the skin surface) and/or evaporation of the aqueous
vehicle (→ reduced hydration of the SC), which both are realistic
conditions applicable to consumer exposure. In spite of differences in
the diffusion-cell design, skin type, vehicle type and applied dose, the
in vitro studies of Marquet et al. (2011), Mørck et al. (2010), and
Kaddar et al. (2008) support the percutaneous penetration estimate of
8.6 % of Demierre et al. (2012), although tending to somewhat lower
values: a rough calculation based on the comparison of permeability
coefficients or the normalization of percutaneous penetration to 24 h
incubation yielded estimates of 2.3 % (Marquet et al., 2011) and 6.5 %
(Mørck et al., 2010) for human skin, and of 4.1 % (Kaddar et al., 2008)
for pig skin.
For exposure scenarios with dermal contact
to thermal paper, the CEF Panel used a conservative value of 10% dermal
absorption. The CEF Panel did not consider skin metabolism (conservative
of the in vitro data between Mørck et al. (2010), Demierre et al. (2012)
and Toner (2015)
Mørck et al. (2010)1
Demierre et al.(2012)1
Number of skin sections
human skin samples from breast surgery
dorsal part of the upper leg from 2 human cadavers.
abdominal skin obtained fresh from surgery from 4 different donors (3 female, 1 male)
Skin Section thickness
Applied volume per area
3995 mg/l (= 17.5 mM)
4 different concentrations:300, 60, 12, 2.4 mg/l
Applied surface density
3, 0.6, 0.12, 0.04μg/cm2
1.9, 0.4, 0.08, 0.015 µg
32 °C ± 1 °C
static Franz diffusion cell
OECD TG 428
flow-through Franz cell
OECD TG 428; SCCS
Skin integrity check
permeability coefficient within acceptance range
electrical resistance > 10.9 kΩ
donor solution (vehicle)
0.9% NaCl + 2% EtOH
Phosphate buffered saline (PBS)
physiol. saline + BSA
DMEM;ca1%, v/v) + UDPGA (2 mM) + PAPS (40 µM).
Duration of incubation
101.5 ± 1.6 %
96.4 – 99.4 %
13.0 ± 5.4 %
8.6 ± 2.1 %
1.7 – 3.6 %
Information derived from EFSA (2015)
into account the above mentioned 10 % dermal penetration taken by EFSA
for their dermal risk assessment based on the ca. 10% Bisphenol A found
in the receptor fluid in the Demierre et al. (2012) study
a significantly lower penetration value into the receptor fluid was
observed in the in vitro dermal penetration study using viable skin (1.7
– 3.6 %). The
approach mentioned in the study request by ECHA to consider the dermis,
epidermis (with stratum corneum) and receptor fluid for further
calculations lead to substantially higher potential penetration values
compared to the EFSA 2015 evaluation of Bisphenol A.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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