Registration Dossier
Registration Dossier
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The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
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EC number: 201-245-8 | CAS number: 80-05-7
Toxicological Summary
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- other: Recent SCOEL Recommendation 2014
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 10 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- Subchronic inhalation study
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- other: Recent SCOEL Recommendation 2014
- DNEL extrapolated from long term DNEL
- Modified dose descriptor starting point:
- NOAEC
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 mg/m³
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- other: Recent SCOEL Recommendation 2014
- Dose descriptor:
- NOAEC
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2 mg/m³
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- other: Recent SCOEL Recommentation 2014
- DNEL extrapolated from long term DNEL
- Dose descriptor starting point:
- NOAEC
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 66 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 75
- Modified dose descriptor starting point:
- BMDL10
- Value:
- 4 978 µg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- See discussion
- AF for differences in duration of exposure:
- 1
- Justification:
- Generation studies up to chronic studies are available.
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Kinetic data is available in a variety of species. Allometric scaling is considered based on AUC values and taken into account to drive the dose descriptor starting point. See discussion for detailed information.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default factor
- AF for intraspecies differences:
- 5
- Justification:
- Default factor
- AF for the quality of the whole database:
- 1
- Justification:
- See discussion
- AF for remaining uncertainties:
- 6
- Justification:
- Factor applied by EFSA (2015) to derive oral TDI – see discussion for more details
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 66 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
- Modified dose descriptor starting point:
- BMDL10
- Justification:
- see discussion
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - workers
Inhalation:
The systemic and local inhalation long-term DNEL for workers are taken from SCOEL recommendation dated June 2014 (SCOEL/SUM/113). SCOEL did not define a STEL value. As a conservative approach short-term and long-term DNEL will be set at the same value; 2 mg/m3.
Dermal:
Local effects:
Bisphenol A is classified as Skin Sens. 1 according to Annex VI of Regulation (EC) No 1272/2008 and allocated to the moderate hazard band. The EU-RAR update 2008 concluded that sensitisation is unlikely at lower concentrations but cannot be excluded at high concentrations:"Overall the new information does not confirm the previously reported evidence of a skin sensitisation potential of Bisphenol A. While the data do not exclude a skin sensitising activity of Bisphenol A at high concentrations (> 30%), there is no evidence that this is a concern for workers in current Bisphenol A manufacturing plants (such workers are believed to represent the group most likely to be exposed to Bisphenol A dust)."
Systemic effects:
Starting point for systemic dermal DNEL calculation:
A BMDL10 of 8 960 μg/kg/day was calculated by EFSA (2015) for changes in the mean relative kidney weight in a two generation toxicity study in mice. This value is taken by EFSA as a starting point for their TDI calculation and is also taken as a starting point for the DNEL calculation.
Correction of the starting point:
Time extrapolation is taken into account because animals were dosed 7 days per week and workers are potentially exposed 5 days per week.
The corrected dermal starting point takes also into account differences in absorption between oral studies in animals and dermal absorption in humans.
Derivation AUCmouse, oral:
EFSA (2015) calculated the AUC (Area under the Curve) of adult mice orally dosed with 100 µg/kg to be 0.244 (nmol x h/l) from a single study. There is a high uncertainty concerning the data reported in this particular study (Doerge et al., 2011). The authors reported that levels of unconjugated Bisphenol A that were above the detection limit were observed only at the earliest three time points, and only in one or two samples out of the twelve determinations at each time. To this, EFSA calculated different scenarios and derived lower-bound (LB), middle-bound (MB), and upper-bound (UB) estimates of the AUC with values ranging from 0.244 – 1.257 (nmol x h/l).
By analyzing and utilizing multiple toxicokinetic data derived under different experimental conditions and over a wide range of doses/species, as this is the case in species scaling approaches, increased confidence can be provided in determining dose and species dependent effects on the toxicokinetics of BPA and likewise, reduces uncertainty. According to the literature available, metabolism, uptake, and distribution of BPA are similar following oral exposures in rodents, monkeys, and humans. For all species investigated, BPA is rapidly cleared from blood and glucuronide conjugates have been measured. Particularly in humans, only low levels of free BPA have been detected, indicating rapid conjugation after oral exposure. Taken together, the available data support that clearance (combination of metabolism and elimination) may scale as a function of bodyweight.
To this, the AUCmouse, oral value was calculated according to a recent species scaling approach (Summit Toxicology, 2020 – Update to Poet & Hays, 2018). A general instruction how to derive the AUCmouse, oral according to this approach is described below.
In general the AUC is correlated to systemic clearance (CL) via the following equation:
(1) AUC = Dose/CL
Clearance (CL) is correlated to body weight (BW) for many compounds according to the following equation:
(2) CL = a x BWb
For the calculation of Clearance equation (2) was used to fit toxicokinetic data from relevant toxicokinetic studies (see Table below). Outliers were identified using the GraphPad Prism ROUT (Robust regression and Outlier removal) method.
| Reference | Species | Dose [mg/kg] | AUCfree (0 ->∞) [nmol*h/L] |
| Tominaga et al., 2006 | Rat | 100.00 | 1611.00 |
| Tominaga et al., 2006 | Monkey | 10.00 | 190.00 |
| Tominaga et al., 2006 | Monkey | 100.00 | 1570.00 |
| Tominaga et al., 2006 | Chimpanzee | 10.00 | 145.00 |
| Sieli et al., 2010 | Mouse | 20.00 | 907.00 |
| Doerge et al., 2010a | Rat | 0.10 | 2.60 |
| Doerge et al., 2010b | Monkey | 0.10 | 1.50 |
| Taylor et al., 2011 | Mouse | 0.40 | 169.61 |
| Taylor et al., 2011 | Monkey | 0.40 | 58.87 |
| Gayrard et al., 2013 | Dog | 20.00 | 1576.94 |
| Teeguarden et al., 2015a | Human | 0.03 | 2.53 |
| Thayer et al., 2015 | Human | 0.10 | 23.00 |
| Gayrard et al., 2019 | Piglet | 100.00 | 1051.20 |
| Sturm et al., 2020 | Sheep | 0.10 | 5.60 |
Fitting the power function equation to the clearance (L/h*kg) as a function of bodyweight for unconjugated BPA in humans, monkeys, mice, chimpanzees, rats, dogs, sheep, and piglets yields values of a= 138.8 and b= -0.015 with good agreement across species. Based on this power function, species-specific CL was calculated according to equation (2) by using a BW of 0.02 kg for mice.
Clmouse, oral [L/h*kg]= 138.8*0.02 -0.015= 147.2 L/h*kg
In a second step, the predicted CL for mouse was used to derive the AUCmouse, oral according to equation (1). To this, a dose of 100 µg/kg (= 438 nmol/kg) was used.
AUCmouse,oral[nmol*h/L]= 438/147.2=2.98 nmol*h/L
This predicted AUC value is taken to derive a corrected dermal starting point for DNEL derivation instead of the value derived by EFSA (2015).
Derivation AUChuman, dermal:
For the derivation of an AUChuman, dermal new recently published data from a human clinical trial is taken into account (Sasso et al., 2020). In this study human volunteers (n=10) were treated dermally on the forearm with 100 µg/kg deuterated Bisphenol A (d6-BPA) over a 12h period, blood and urine samples were taken from the beginning of dosing through a three- or six-day period. Time-course serum and urine concentrations for total and unconjugated d6-BPA are presented and terminal half-lives and respective AUCs are calculated. For the AUChuman, dermal(0->∞) of free d6-BPA a value of 7.51 nmol*h is reported. This value is taken to derive a corrected dermal starting point for DNEL derivation.
Calculation of corrected starting point:
Starting point: BMDL10 =8 960 μg/kg bw/day
Time correction: 7/5
AUCoral, mice (100 µg/kg) = 2.98 nmol x h/l
AUCdermal, human (100 µg/kg) = 7.51 nmol x h/l
Corrected starting point = 8 960 μg/kg bw/day x 7/5 x 2.98/7.51 = 4978 μg/kg bw/day
Assessment factors:
Interspecies differences (toxicokinetics): 1
Differences in toxicokinetics after oral dosing in mice and potential dermal human exposure is taken into account to derive the corrected starting point.
Interspecies differences (additional uncertainty): 2.5
2.5 is the REACH guidance default factor. This factor is also applied by EFSA (2015).
Intraspecies factor (worker): 5
5 is the REACH guidance default factor. This factor should be considered conservative based a recent PB-PK model reported by Yang et al., (2015. Toxicol. Appl. Pharmacol.). The authors conclude concerning the interspecies factor in the general population:“In this study, the recalibrated human Bisphenol A PBPK model was used to estimate the inter-individual variability of internal dose metrics of Bisphenol A for the general population based on the estimated daily intake of Bisphenol A in the United States (FDA 2014b; Lakind and Naiman 2008). Model predicted peak serum Bisphenol A levels fell within the range of pM, with 95% of human variability ranged within an order of magnitude, suggesting that an uncertainty factor of less than 10 would be reasonable to account for the inter-individual variability in pharmacokinetics.”
Additional uncertainty: 6
EFSA applied an additional factor of 6 for the t-TDI derivation for the general population. EFSA defined a HED of 609 μg/kg/day based on the BMDL10 of 8 960 μg/kg/day for kidney weight in the mice 2-generation study (Tyl et al., 2008) and toxicokinetic differences in mice and humans. EFSA evaluated all available data in a weight-of-evidence approach and considered all other endpoints, with one exception, to be “less than likely” in their hazard evaluation.
EFSA (2015) assigned a likelihood level of “likely” to Bisphenol A induced proliferative changes in the mammary gland. No BMDL10 could be calculated for mammary gland effects based on the Delclos (2014) study. As outlined in the chapter “Carcinogenicity” the authors of this study and independent pathologists concluded:"Taking the incidences, the statistical testing results, and all pathologists and study authors opinions together, the authors of the NTP report (Gu and Mitkus, 2013), concluded that the evidence for duct hyperplasia in the mammary gland of females on either PND 21 or PND 90 was weak. They considered it an equivocal finding that may be the reflection of normal variability and/or a reflection of limits in tissue processing. Bisphenol A did not cause duct hyperplasia in the mammary glands of male rats, while conversely the reference estrogen EE2 induced hyperplasia in the male but not the female mammary gland."
EFSA performed an uncertainty evaluation and defined the dose range which approached “likely” in the (HED) to be 100–1000 μg/kg bw per day. This dose range covers the HED of 609 μg/kg/day derived for kidney toxicity and used as a starting point for the t-TDI derivation for the general population. EFSA defined an uncertainty factor of 6 for the general population to cover the lower border of the 10-fold dose range which approached “likely”.
As an conservative approach we included this uncertainty factor of 6 for the DNEL derivation of the general population and workers, however we consider it as overconservative as no health effect is attributed to this assessment factor of 6 and the induced proliferative changes in the mammary gland identified by EFSA in 2015 were considered as an equivocal finding that may be the reflection of normal variability by the NCTR/NTP study authors. In line, also in the largest-ever scientific investigation of Bisphenol A, the CLARITY Core study, no consistent effect on proliferative changes in the mammary gland were observed, which supports this conclusion.
The overall assessment factor considered for worker dermal DNEL derivation is: 5 x 2.5 x 6 = 75
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- other: based on SCOEL Recommendation 2014
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 10 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- subchronic inhalation study
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- By inhalation
DNEL related information
- DNEL derivation method:
- other: based on SCOEL Recommendation 2014
- DNEL extrapolated from long term DNEL
- Modified dose descriptor starting point:
- NOAEC
Local effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/m³
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- other: based on SCOEL Recommendation 2014
- Dose descriptor:
- NOAEC
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/m³
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- other: based on SCOEL Recommendation 2014
- DNEL extrapolated from long term DNEL
- Dose descriptor starting point:
- NOAEC
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 24 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 150
- Modified dose descriptor starting point:
- BMDL10
- Value:
- 3 555 µg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- Default factor
- AF for differences in duration of exposure:
- 1
- Justification:
- Default factor
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Kinetic data is available in a variety of species. Allometric scaling is considered based on AUC values and taken into account to drive the dose descriptor starting point. See discussion for detailed information.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default factor
- AF for intraspecies differences:
- 10
- Justification:
- Default factor
- AF for the quality of the whole database:
- 1
- Justification:
- Default factor
- AF for remaining uncertainties:
- 6
- Justification:
- Factor applied by EFSA (2015) to derive oral TDI – see discussion for more details
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 24 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL extrapolated from long term DNEL
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- sensitisation (skin)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 53 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 150
- Modified dose descriptor starting point:
- other: human equivalent dose (HED)
- Value:
- 7 947 µg/kg bw/day
- AF for dose response relationship:
- 1
- Justification:
- EFSA 2015
- AF for differences in duration of exposure:
- 1
- Justification:
- EFSA 2015
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- Kinetic data is available in a variety of species. Allometric scaling is considered based on AUC values and taken into account to drive the dose descriptor starting point. See discussion for detailed information.
- AF for other interspecies differences:
- 2.5
- Justification:
- EFSA 2015
- AF for intraspecies differences:
- 10
- Justification:
- EFSA 2015
- AF for the quality of the whole database:
- 1
- Justification:
- EFSA 2015
- AF for remaining uncertainties:
- 6
- Justification:
- Factor applied by EFSA (2015) to derive oral TDI – see discussion for more details
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 53 µg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - General Population
Inhalation:
An inhalation DNEL(worker) of 2 mg/m3 is taken based on the SCOEL recommendation for an OEL of 2 mg/m3 for worker covering local and potential systemic effects (SCOEL/SUM/113; June 2014). According to the REACH Guidance documents there is a factor of 2 between the intraspecies differences for worker (5) and intraspecies variability for the general population (10). This factor is applied to the worker DNEL of 2 mg/m3 and results in a DNEL for the general population of 1 mg/m3.
As a conservative approach short-term and long-term DNEL will be set at the same value; 1 mg/m3.
This value of 1 mg/m3 based on the SCOEL recommendation is supported by a supplemental derivation of the inhalation DNEL (general population) according to ECHA guidance (see below).
Supplemental Derivation of the DNELinhalative, systemic for general population:
As Starting point a NOAEC based on systemic toxicity is derived from a sub chronic inhalation toxicity study (Nitschke et al., 1988). In accordance with the recent recommendation of SCOEL (2014) no evidence for systemic toxicity was observed in this study and therefore, the highest tested concentration of 150 mg/m3 is chosen as NOAEC for systemic toxicity. Time extrapolation needs to be taken into account as for the general population an exposure of 24 hours per day and 7 days per week is assumed, however in Nitschke et al., 1988 treatment was conducted 6 hours per day and 5 days per week. Interspecies differences allometric scaling is already included in this inhalation study and in the correction of exposure a default value of 2.5 is required according to ECHA Guidance. Moreover, a default factor of 10 is chosen for intraspecies differences, a factor of 1 for Dose-response/endpoint-specific/severity issue and for Quality of Database. Based on the available literature there is no evidence for i) systemic toxicity at concentrations already leading to local effects in the nasal cavity and ii) time-dependency of any observed efffect based on available subacute and subchronic studies. Therefore, a factor of 1 for differences in duration of exposure is determined.
Calculation of corrected starting point:
Starting point: NOAEC (systemic toxicity)= 150 mg/m3
Time correction: 6h/24h x 5d/7d
Corrected starting point= 150 mg/m3 x 6h/24h x 5d/7d= 26,8 mg/m3
| Assessment Factor | Value |
| Interspecies differences | 2.5 |
| Intraspecies differences | 10 |
| Dose-response/endpoint specific/severity issue | 1 |
| Quality of whole database | 1 |
| Differences in duration of exposure | 1 |
| Overall Assessment Factor | 25 |
Supplemental DNELinhalative, systemic= 26,8/25 = 1,08 mg/m3≈ 1mg/m3
This shows that a derivation of the DNELsystemic, inhalative for general population according to ECHA guidance results in the same value as the derivation based on the SCOEL recommendation in 2014.
Dermal:
Local effects:
Bisphenol A is classified as Skin Sens. 1 according to Annex VI of Regulation (EC) No 1272/2008 and allocated the moderate hazard band. The EU-RAR update 2008 concluded that sensitisation is unlikely at lower concentrations but cannot be excluded at high concentrations:"Overall the new information does not confirm the previously reported evidence of a skin sensitisation potential of Bisphenol A. While the data do not exclude a skin sensitising activity of Bisphenol A at high concentrations (> 30%), there is no evidence that this is a concern for workers in current Bisphenol A manufacturing plants (such workers are believed to represent the group most likely to be exposed to Bisphenol A dust)."
Systemic effects:
Starting point for systemic dermal DNEL calculation:
A BMDL10 of 8 960 μg/kg/day was calculated by EFSA (2015) for changes in the mean relative kidney weight in a two generation toxicity study in mice. This value is taken by EFSA as a starting point for their TDI calculation and is also taken as a starting point for the DNEL calculation.
Correction of the starting point:
The corrected dermal starting point takes into account differences in absorption between oral studies in animals and dermal absorption in humans.
Derivation AUCmouse, oral:
EFSA (2015) calculated the AUC (Area under the Curve) of adult mice orally dosed with 100 µg/kg to be 0.244 (nmol x h/l) from a single study. There is a high uncertainty concerning the data reported in this particular study (Doerge et al., 2011). The authors reported that levels of unconjugated Bisphenol A that were above the detection limit were observed only at the earliest three time points, and only in one or two samples out of the twelve determinations at each time. To this, EFSA calculated different scenarios and derived lower-bound (LB), middle-bound (MB), and upper-bound (UB) estimates of the AUC with values ranging from 0.244 – 1.257 (nmol x h/l).
By analyzing and utilizing multiple toxicokinetic data derived under different experimental conditions and over a wide range of doses/species, as is the case in species scaling approaches, increased confidence can be provided in determining dose and species dependent effects on the toxicokinetics of BPA and likewise, reduces uncertainty. According to the literature available, metabolism, uptake, and distribution of BPA are similar following oral exposures in rodents, monkeys, and humans. For all species investigated, BPA is rapidly cleared from blood and glucuronide conjugates have been measured. Particularly in humans, only low levels of free BPA have been detected, indicating rapid conjugation after oral exposure. Taken together, the available data support that clearance (combination of metabolism and elimination) may scale as a function of bodyweight.
Based on these information the AUCmouse, oral value was calculated according to a recent species scaling approach (Summit Toxicology, 2020 – Update to Poet & Hays, 2018). A general instruction how to derive the AUCmouse, oral according to this approach is described below.
In general the AUC is correlated to systemic clearance (CL) via the following equation:
(1) AUC = Dose/CL
Clearance (CL) is correlated to body weight (BW) for many compounds according to the following equation:
(2) CL = a x BWb
For the calculation of Clearance equation (2) was used to fit toxicokinetic data from relevant toxicokinetic studies (see Table below). Outliers were identified using the GraphPad Prism ROUT (Robust regression and Outlier removal) method.
| Reference | Species | Dose [mg/kg] | AUCfree(0 ->∞)[nmol*h/L] |
| Tominaga et al., 2006 | Rat | 100.00 | 1611.00 |
| Tominaga et al., 2006 | Monkey | 10.00 | 190.00 |
| Tominaga et al., 2006 | Monkey | 100.00 | 1570.00 |
| Tominaga et al., 2006 | Chimpanzee | 10.00 | 145.00 |
| Sieli et al., 2010 | Mouse | 20.00 | 907.00 |
| Doerge et al., 2010a | Rat | 0.10 | 2.60 |
| Doerge et al., 2010b | Monkey | 0.10 | 1.50 |
| Taylor et al., 2011 | Mouse | 0.40 | 169.61 |
| Taylor et al., 2011 | Monkey | 0.40 | 58.87 |
| Gayrard et al., 2013 | Dog | 20.00 | 1576.94 |
| Teeguarden et al., 2015a | Human | 0.03 | 2.53 |
| Thayer et al., 2015 | Human | 0.10 | 23.00 |
| Gayrard et al., 2019 | Piglet | 100.00 | 1051.20 |
| Sturm et al., 2020 | Sheep | 0.10 | 5.60 |
Fitting the power function equation to the clearance (L/h*kg) as a function of bodyweight for unconjugated BPA in humans, monkeys, mice, chimpanzees, rats, dogs, sheep, and piglets yields values of a= 138.8 and b= -0.015 with good agreement across species. Based on this power function, species-specific CL was calculated according to equation (2) by using a BW of 0.02 kg for mice.
CLmouse, oral [L/h*kg]= 138.8*0.02 -0.015= 147.2 L/h*kg
In a second step, the predicted CL for mouse was used to derive the AUCmouse, oral according to equation (1). To this, a dose of 100 µg/kg (= 438 nmol/kg) was used
AUCmouse,oral [nmol*h/L]= 438/147.2= 2.98 nmol*h/L
This predicted AUC value is taken to derive a corrected dermal starting point for DNEL derivation instead of the value derived by EFSA (2015).
For the derivation of an AUChuman, dermal new recently published data from a human clinical trial are taken into account (Sasso et al., 2020). In this study human volunteers (n=10) were treated dermally on the forearm with 100 µg/kg deuterated Bisphenol A (d6-BPA) over a 12h period, blood and urine samples were taken from the beginning of dosing through a three- or six-day period. Time-course serum and urine concentrations for total and unconjugated d6-BPA are presented and terminal half-lives and respective AUCs are calculated. For the AUChuman, dermal(0->∞) of free d6-BPA a value of 7.51 nmol*h is reported. This value is taken to derive a corrected dermal starting point for DNEL derivation.
Calculation of corrected starting point:
Starting point: BMDL10 =8 960 μg/kg bw/day
AUCoral, mice (100 µg/kg) = 2.98 nmol x h/l
AUCdermal, human (100 µg/kg) = 7.51 nmol x h/l
Corrected starting point = 8 960 μg/kg bw/day x 2.98/7.51 = 3555 μg/kg bw/day
Assessment factors:
Interspecies differences (toxicokinetics): 1
Differences in toxicokinetics after oral dosing in mice and potential dermal human exposure is taken into account to derive the corrected starting point.
Interspecies differences (additional uncertainty): 2.5
2.5 is the REACH guidance default factor. This factor is also applied by EFSA (2015).
Intraspecies factor (general population): 10
10 is the REACH guidance default factor. This factor should be considered conservative based a recent PB-PK model reported by Yang et al., (2015. Toxicol. Appl. Pharmacol.). The authors conclude concerning the interspecies factor in the general population:“In this study, the recalibrated human Bisphenol A PBPK model was used to estimate the inter-individual variability of internal dose metrics of Bisphenol A for the general population based on the estimated daily intake of Bisphenol A in the United States (FDA 2014b; Lakind and Naiman 2008). Model predicted peak serum Bisphenol A levels fell within the range of pM, with 95% of human variability ranged within an order of magnitude, suggesting that an uncertainty factor of less than 10 would be reasonable to account for the inter-individual variability in pharmacokinetics.”
Additional uncertainty: 6
EFSA applied an additional factor of 6 for the t-TDI derivation for the general population. EFSA defined a HED of 609 μg/kg/day based on the BMDL10 of 8 960 μg/kg/day for kidney weight in the mice 2-generation study (Tyl et al.,2008) and toxicokinetic differences in mice and humans. EFSA evaluated all available data in a weight-of-evidence approach and considered all other endpoints, with one exception, to be “less than likely” in their hazard evaluation.
EFSA (2015) assigned a likelihood level of “likely” to Bisphenol A induced proliferative changes in the mammary gland. No BMDL10 could be calculated for mammary gland effects based on the Delclos (2014) study. As outlined in the chapter “Carcinogenicity” the authors of this study and independent pathologists concluded: "Taking the incidences, the statistical testing results, and all pathologists and study authors opinions together, the authors of the NTP report (Gu and Mitkus, 2013), concluded that the evidence for duct hyperplasia in the mammary gland of females on either PND 21 or PND 90 was weak. They considered it an equivocal finding that may be the reflection of normal variability and/or a reflection of limits in tissue processing. Bisphenol A did not cause duct hyperplasia in the mammary glands of male rats, while conversely the reference estrogen EE2 induced hyperplasia in the male but not the female mammary gland."
EFSA performed an uncertainty evaluation and defined the dose range which approached “likely” in the (HED) to be 100–1000 μg/kg bw per day. This dose range covers the HED of 609 μg/kg/day derived for kidney toxicity and used as a starting point for the t-TDI derivation for the general population. EFSA defined an uncertainty factor of 6 for the general population to cover the lower border of the 10-fold dose range which approached “likely”.
As an conservative approach we included this uncertainty factor of 6 for the DNEL derivation of the general population and workers, however we consider it as overconservative as no health effect is attributed to this assessment factor of 6 and the induced proliferative changes in the mammary gland identified by EFSA in 2015 were considered as an equivocal finding that may be the reflection of normal variability by the NCTR/NTP study authors. In line, also in the largest-ever scientific investigation of Bisphenol A, the CLARITY Core study, no consistent effect on proliferative changes in the mammary gland were observed, which supports this conclusion.
The overall assessment factor considered for general population dermal DNEL derivation is: 10 x 2.5 x 6 = 150
Oral:
Starting point for systemic oral DNEL calculation:
A BMDL10 of 8 960 μg/kg/day was calculated by EFSA (2015) for changes in the mean relative kidney weight in a two generation toxicity study in mice. This value is taken by EFSA as a starting point for their TDI calculation and is also taken as a starting point for the DNEL calculation.
Correction of the starting point:
EFSA (2015) used the so called Human Equivalent Dose concept for extrapolation from animal experiment to a human equivalent dose. This concept is also used for the derivation of the DNELoral for general population.
Derivation AUCmouse, oral:
The AUCmouse, oral value was calculated according to a recent species scaling approach (Summit Toxicology, 2020 – Update to Poet & Hays, 2018). A general instruction how to derive the AUCmouse, oral according to this approach is described above (see additional information DNELdermal for general population).
Derivation AUChuman, oral:
EFSA (2015) simulated the AUC (Area under the Curve) of human orally dosed with 100 µg/kg to be 3.6 (nmol x h/l) from a PBPK model based on life stage-specific kinetic data in monkey and rat, which are scaled up to the human situation (Yang et al., 2013). In the meantime, human exposure data became available from two recently published studies (Thayer et al., 2015; Teeguarden et al., 2015).
Relying on one particular study would directly lead to the acceptance of variabilities in the experimental setup, the dosing and the sampling procedures. Instead the already addressed species scaling approach is preferred as by analyzing and utilizing multiple toxicokinetic data derived under different experimental conditions and over a wide range of doses/species increased confidence can be provided (Summit Toxicology, 2020 – Update to Poet & Hays, 2018). A general instruction how to derive an species specific AUC according to this approach is described above (see additional information DNELdermal for general population). For the derivation of an AUChuman, oral a bodyweight of 70kg and a dose of 100 µg/kg (=438 nmol/kg) are assumed.
CLhuman, oral [L/h*kg]= 138.8*70-0.015= 130.2 L/h*kg
AUChuman, oral [nmol*h/L]= 438/130.2= 3.36 nmol*h/L
This predicted AUC value is taken to derive a HED for DNEL derivation instead of the value derived by EFSA (2015).
Calculation of Human Equivalent Dose (HED):
Starting point: BMDL10 =8 960 μg/kg bw/day
AUCoral, mice (100 µg/kg) = 2.98 nmol x h/l
AUCdermal, human (100 µg/kg) = 3.36 nmol x h/l
Human Equivalent Dose Factor (HEDf)= 2.98 nmol*L/3.36nmol*L= 0.9
HED = 8 960 μg/kg bw/day x 2.98/3.36 = 7947 μg/kg bw/day
Assessment factors:
Interspecies differences (toxicokinetics): 1
Differences in toxicokinetics after oral dosing in mice and potential oral human exposure is taken into account to derive a Human Equivalent Dose.
Interspecies differences (additional uncertainty): 2.5
2.5 is the REACH guidance default factor. This factor is also applied by EFSA (2015).
Intraspecies factor (general population): 10
10 is the REACH guidance default factor. This factor should be considered conservative based a recent PB-PK model reported by Yang et al., (2015. Toxicol. Appl. Pharmacol.). The authors conclude concerning the interspecies factor in the general population:“In this study, the recalibrated human Bisphenol A PBPK model was used to estimate the inter-individual variability of internal dose metrics of Bisphenol A for the general population based on the estimated daily intake of Bisphenol A in the United States (FDA 2014b; Lakind and Naiman 2008). Model predicted peak serum Bisphenol A levels fell within the range of pM, with 95% of human variability ranged within an order of magnitude, suggesting that an uncertainty factor of less than 10 would be reasonable to account for the inter-individual variability in pharmacokinetics.”
Additional uncertainty: 6
EFSA applied an additional factor of 6 for the t-TDI derivation for the general population. EFSA defined a HED of 609 μg/kg/day based on the BMDL10 of 8 960 μg/kg/day for kidney weight in the mice 2-generation study (Tyl et al.,2008) and toxicokinetic differences in mice and humans. EFSA evaluated all available data in a weight-of-evidence approach and considered all other endpoints, with one exception, to be “less than likely” in their hazard evaluation.
EFSA (2015) assigned a likelihood level of “likely” to Bisphenol A induced proliferative changes in the mammary gland. No BMDL10 could be calculated for mammary gland effects based on the Delclos (2014) study. As outlined in the chapter “Carcinogenicity” the authors of this study and independent pathologists concluded: "Taking the incidences, the statistical testing results, and all pathologists and study authors opinions together, the authors of the NTP report (Gu and Mitkus, 2013), concluded that the evidence for duct hyperplasia in the mammary gland of females on either PND 21 or PND 90 was weak. They considered it an equivocal finding that may be the reflection of normal variability and/or a reflection of limits in tissue processing. Bisphenol A did not cause duct hyperplasia in the mammary glands of male rats, while conversely the reference estrogen EE2 induced hyperplasia in the male but not the female mammary gland."
EFSA performed an uncertainty evaluation and defined the dose range which approached “likely” in the (HED) to be 100–1000 μg/kg bw per day. This dose range covers the HED of 609 μg/kg/day derived for kidney toxicity and used as a starting point for the t-TDI derivation for the general population. EFSA defined an uncertainty factor of 6 for the general population to cover the lower border of the 10-fold dose range which approached “likely”.
As an conservative approach we included this uncertainty factor of 6 for the DNEL derivation of the general population and workers, however we consider it as overconservative as no health effect is attributed to this assessment factor of 6 and the induced proliferative changes in the mammary gland identified by EFSA in 2015 were considered as an equivocal finding that may be the reflection of normal variability by the NCTR/NTP study authors. In line, also in the largest-ever scientific investigation of Bisphenol A, the CLARITY Core study, no consistent effect on proliferative changes in the mammary gland were observed, which supports this conclusion.
The overall assessment factor considered for general population dermal DNEL derivation is: 10 x 2.5 x 6 = 150
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