Registration Dossier

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
DNEL 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:
0.031 mg/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):
12.5
Modified dose descriptor starting point:
BMDL10
DNEL value:
387 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 chroni studies are available.
AF for interspecies differences (allometric scaling):
1
Justification:
Kinetic data are available in mice, rats and monkeys. 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:
1
Justification:
See discussion
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.031 mg/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:
NOAEL

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 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 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 BMDL(10) 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 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 into account differences in absorption between oral studies in animals and dermal absorption in humans.

 

AUC mice orally dosed with 100 µg/kg:

EFSA (2015) calculated the AUC of adult mice orally dosed with 100 µg/kg to be 0.244 (nmol x h/l). 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. 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).

 

Based on above mentioned limitations of this study an alternative approach was conducted to derive AUC values for mice applying species scaling.

 

In general AUC is correlated to systemic clearance (CL) via the following equation: AUC = dose/CL

CL is correlated to body weight (BW) for many compounds according to the following equation:

CL = a x BWb

 

Studies with relevant Toxicokinetic data are summarised below:

Reference

 

Species

 

Dose (mg/kg)

 

AUCFree(0--∞) (nmol/hr/L)

 

Doerge et al., 2011. Toxicol. Lett. 207, 298–305

mouse

0.1

0.1

Doerge et al., 2010. Toxicol. Appl. Pharmacol. 247, 158–65

rat

0.1

2.6

Doerge et al., 2010. Toxicol.

Appl. Pharmacol. 248, 1–11.

monkey

0.1

1.5

Gayrard et al., 2013. Environ.

Health Perspect. 121, 951–6

dog

20

1577

Sieli et al., 2011. Environ.

Health Perspect. 119, 1260–5

mouse

20

919

Tominaga et al., 2006. Toxicology 226, 208–17.

 

Rat

 

 

Monkey

 

 

chimpanzee

10

100

 

10

100

 

10

49

2431

 

189

1596

 

148

Taylor et al., 2011. Environ.

Health Perspect. 119, 422–30

 

Mouse

 

 

monkey

0.4

100

 

0.4

170

1.3e4

 

59

Teeguarden et al., 2015. Toxicol. Appl. Pharmacol. 288, 131-142

human

0.03

2.5

Thayer et al., 2015. Environ.

Int. 83, 107–115.

human

0.1

23

 

Fitting the power function equation to the AUC for unconjugated Bisphenol A in humans, monkeys, mice, chimpanzees, dogs and rats yields values of 35.6 for “a” and 0.92 for “b” with good agreement across species (r2= 0.95 excluding the mice data by Doerge et al., 2011). See Figure 1 and 2 in the attached documentation for more details. Based on this evaluation the predicted AUC for mice (dosed with 100 µg/kg) is 2.9 nmol x h/l.

 

This predicted values is taken to derive a corrected dermal starting point for DNEL derivation instead of the value derived by EFSA (2015) since 1) high uncertainty concerning the data reported in Doerge et al., 2011 is recognized by EFSA and 2) additional human data became available after the EFSA evaluation in 2015 (Teeguarden 2015, Thayer 2015) which fit the species scaling approach.

 

Calculated human dermal AUC (100 µg/kg):

PB-PK models for humans after dermal exposure are reported by Mielke et al (2011. Toxicology Letters. 204, 190-198) and Fischer et al (2011. Toxicology and Applied Pharmacology. 257. 122-136). Mielke et al reported an AUC of 697 (pg/ml x h) after dosing with 0.97 µg/kg/day (taking into account 100% absorption through the skin). Scaling this AUC to a dose of 100 µg/kg results in an AUC of 314 (nmol x h/l). Similar data are reported by Fisher (2011)The relationship between the two PBPK models for dermal AUCs is: AUCdermal,Fisher/Yang = 0.94 x AUCdermal,Mielke (see p. 585 of PART II in EFSA 2015).

A calculated dermal AUC value of 314 (nmol x h/l) is taken to derive a corrected dermal starting point for DNEL derivation.

 

Dermal absorption rate in humans.

To derive a dermal absorption rate an in vitro dermal absorption and metabolism study was conducted upon request by ECHA (Toner et al 2015). A summary of the mean results is provided in the following table:

 

Target Concentration (mg/L)

300

60

12

2.4

 

(% Applied Dose)

Total Dislodgeable Dose

72.34±5.64

70.91±6.20

71.95±7.98

71.57±9.11

WholeStratum Corneum

10.25±5.44

9.25±4.30

7.31±3.33

7.70±4.92

Total Unabsorbed Dose

82.61±8.37

80.31±6.92

79.33±9.97

79.37±9.91

Epidermis

10.66±6.40

10.45±5.73

10.38±5.36

11.91±4.86

Dermis

3.28±2.44

3.97±1.99

6.19±4.28

4.51±3.73

Total Absorbed Dose

1.98±1.42

1.68±1.20

2.72±1.95

3.62±1.69

Dermal Delivery

15.92±8.14

16.10±7.01

19.28±8.54

20.04±6.24

Mass Balance

98.53±1.99

96.41±1.45

98.62±2.18

99.40±6.54

Total Dislodgeable Dose = skin wash + tissue swabs + pipette tips + donor chamber wash

Unabsorbed Dose = dislodgeable dose + wholestratum corneum (all tape strips+ unexposed skin

Absorbed Dose = receptor fluid + receptor chamber wash + receptor rinse

Dermal Delivery = epidermis + dermis + absorbed dose

Mass balance = dermal delivery + unabsorbed dose

 

Overall, the majority of the applied radioactivity was associated with epidermis samples (10.66%) compared to dermis (3.28%) and receptor fluid (1.98%) samples.

 

Applying the EFSA Guidance on Dermal Absorption (EFSA Journal 2012. 10, 2665) or SCCS Basic Criteria for the in vitro assessment of dermal absorption of cosmetic ingredients (SCCS/1358/1) the potentially bioavailable portion of Bisphenol A is ca. 30% over the whole dose range tested.

 

EFSA guidance (data provided as % applied dose)

Test Preparation

Mean Potentially Absorbable Dose

Mean+1SD

SD>25% of mean

300 mg/L

23.70

31.84

Yes

60 mg/L

23.09

29.13

Yes

12 mg/L

24.80

31.79

Yes

2.4 mg/L

25.42

30.79

No

Bold values denotes value to be used according to the EFSA Guidance. (For more detail see chapter Toxicokinetics).

 

SCCS criteria (data provided as % applied dose)

Test Preparation

Mean dermal delivery

Mean+1SD

Mean+2SD

 300 mg/L

15.92

24.06

32.20

 60 mg/L

16.10

23.11

30.12

12 mg/L

19.28

27.82

36.36

2.4 mg/L

20.04

26.28

31.59

No clear guidance is given on guideline to define if 1 or 2 SD should be used.

 

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 (<25%). Metabolites 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 some in vitro metabolic capacity but further experiments may be necessary to optimize the experimental conditions to quantify that metabolism.

Overall,a potentially bioavailable portion of Bisphenol A of 30% is taken to derive a corrected dermal starting point for DNEL derivation. As a conservative approach no metabolism was taken into account. As outlined in the chapter "Toxicokinetics", taking into account the 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 this 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.

 

Comparison of calculated AUC human dermal dosed with 100 µg/kg with experimental data indicate that the derived values are conservative.

Taking into account the above mentioned calculated AUC value of 314 (nmol x h/l) and 30% dermal absorption and no metabolism an internal AUC of 314 x 0.3 = 94.2 nmol x h/l can be calculated.

Recent information on a human toxicokinetic study is available (Thayer KA, Doerge DR, Hunt D, Schurman S, Twaddle NC, Churchwell MI, Garantziotis S, Kissling GE, Easterling MR, Bucher JR and Birnbaum LS (2014a) Pharmacokinetics of Bisphenol A in Humans Following Dermal Administration. Preliminary results. Submitted information via public consultation on the restriction proposal to ECHA. Comment reference number 1043. Public comments are available athttp://echa.europa.eu/restrictions-under-consideration/-/substance-rev/1894/term) 

The authors report data on a 3-day pilot study of 2 men and 2 women treated with 100 μg/kg bw of deuterated Bisphenol A (d-BPA) by dermal (forearm) administration in a suspension using 0.3% carboxymethylcellulose (CMC) as a vehicle housed under a Hill Top Chamber. These subjects also participated in a recently completed oral PK study using the administered dose level (Thayer et al., 2015. Environ. Int. 83, 107–115). The use of d-BPA allowed administered d-BPA to be distinguished from background native (unlabelled) Bisphenol A. The following results are reported: “The AUCs for total and aglycone d-BPA following dermal administration were compared in the same subjects after oral dosing with the same administered dose (100 μg/kg bw).The AUC following dermal administration was 0.002-1.2% of the AUC following oral administration for total d-BPA and 0.05-43% for aglycone d-BPA.

 

Comparing the oral AUC of 23 nmol x hr/L reported for dosing with 100 µg/kg within the same volunteers by Thayer et al (2015) and the calculated dermal AUC of 94.2 nmol x h/l (adjusted to 100 µg/kg and taking into account 30% adsorption) it can be concluded that the calculated dermal AUC is higher than the oral AUC and, consequently, should be regarded as very conservative.

 

Calculation of corrected starting point:

Starting point: BMDL(10) =8 960 μg/kg/day

Time correction 7/5

AUC oral mice (100 µg/kg) = 2.9 nmol x h/l

AUC dermal human (100 µg/kg) = 94.2 nmol x h/l

Corrected starting point = 8 960 μg/kg/day x 7/5 x 2.9/94.2 = 387 μg/kg/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. In press). 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: 1

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 BMDL(10) of 8 960 μg/kg/day for kidney weight in the mice 2-generation study (Tyl 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”. We followed this approach for the DNEL derivation of the general population, but consider this approach as overprotective for worker since the HED for kidney effects is in this dose range, no health-effect is attributed to the additional assessment factor of 6 but only overall uncertainty and the induced proliferative changes in the mammary gland identified by EFSA as “likely” is considered as an equivocal finding by the NCTR/NTP study authors and pathologists.

 

The overall assessment factor considered for worker dermal DNEL derivation is: 5 x 2.5 = 12.5

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
DNEL 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
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
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:
0.002 mg/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
DNEL value:
275.8 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:
Default factor
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
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.002 mg/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:
0.004 mg/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)
DNEL value:
609 µg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
EFSA defined a t-TDI in 2015
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:
EFSA 2015
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:
EFSA 2015
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.004 mg/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.

 

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:

See discussion on worker DNEL; a BMDL(10) of 8 960 μg/kg/day is taken by EFSA as a starting point for their TDI calculation and also taken as a starting point for the DNEL calculation.

 

Correction of the starting point:

See discussion on worker DNEL

Based on a species scaling approach a calculated AUC oral mice (100 µg/kg) = 2.9 nmol x h/l is taken to derive a corrected dermal starting point.

Taking into account the above mentioned calculated AUC value of 314 (nmol x h/l) by Mielke et al., 2011, 30% dermal absorption and no metabolism an internal AUC of 314 x 0.3 = 94.2 nmol x h/l is taken forward.

Corrected BMDL(10) as a starting point for the general population can be calculated as follows: 8 960 μg/kg/day x 2.9/94.2 = 275.8 μg/kg/day

 

Assessment factors derived by EFSA are applied:

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 is also applied by EFSA (2015).

This factor should be considered conservative based a recent PB-PK model reported by Yang et al., (2015. Toxicol. Appl. Pharmacol. In press). 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 BMDL(10) of 8 960 μg/kg/day for kidney weight in the mice 2-generation study (Tyl 2008) and toxicokinetik 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”. We followed this approach for the DNEL derivation of the general population, but consider this approach as overprotective since the HED for kidney effects is in this dose range, no health-effect is attributed to the additional assessment factor of 6 but only overall uncertainty and the induced proliferative changes in the mammary gland identified by EFSA as “likely” is considered as an equivocal finding be the NCTR/NTP study authors and pathologists.

 

The overall assessment factor considered for the general population DNEL derivation is: 2.5 x 10 x 6 = 150

Oral:

The temporary TDI of 4 µg/kg/day derived by EFSA in 2015 is taken as the oral DNEL. As a conservative approach short-term and long-term DNEL will be set at the same value.