Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29.39 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
15
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
104.15 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Value:
8.3 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
21
Dose descriptor starting point:
other: NOAEL

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Bisphenol F Diglycidylether (BPFDGE) was positive for the induction of dermal sensitization in the mouse Local Lymph Node Assay (LLNA). Based on an EC3 value of 0.7% BPFDGE is considered to be a strong dermal sensitizer. Following ECHA guidance this EC3 value is converted to an EC3 value of 175 ug/cm2 and is considered the LOAEL for the induction of dermal sensitization the mouse LLNA for BPFDGE. 

- DERMAL - ACUTE LOCAL

   Dose descriptor = EC3 of 0.7%; from a well described mouse LLNA study.

 

-  Modification of dose descriptor:

     = 0.7% * (250 ug/cm2/%)

   dermal EC3 = 175 ug/cm2

 

-  Adjustment factors (ECETOC Technical Report #86): 

Criteria

Adjustment Factor

Allometric scaling - mouse

7

Intraspecies - workers

3

Overall Adjustment Factor

21

 

-  DNEL calculation

   DNEL dermal = dermal NOAEL / (adjustment factors)

   DNEL dermal = 175 ug/cm2 / (21)

   DNEL dermal = 8.33 ug/cm2

   The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat sub\chronic NOAEL. The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:

·  Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.

·  Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.

   Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that “Care should be taken to avoid double counting several aspects when multiplying the individual factors.” Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in “double counting”, and if used inappropriately, would lead to a large, conservative overall assessment factor. In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs.

 

- Critical NOAEL used = rabbit oral NOAEL 250 mg/kg/day (13-week oral subchronic repeat dose study – systemic)

- Absorption rates: 10% dermal, 100% oral, and 100% inhalation regardless of species

DERMAL - SYSTEMIC

   Dose descriptor = NOAEL of 250 mg/kg/day; from a well described 13-week oral subchronic repeat dose study.

 

-  Modification of dose descriptor:

   = oral NOAEL * (rat oral absorption rate / human dermal absorption rate)

   = 250 * (100% / 10%)

   dermal NOAEL = 2500 mg/kg/day

 

-  Adjustment factors (ECETOC Technical Report #86): 

Criteria

Adjustment Factor

Allometric scaling - rat

4

Intraspecies - workers

3

Subchronic study to Chronic

2

Overall Adjustment Factor

24

 

-  DNEL calculation

   DNEL dermal = dermal NOAEL / (adjustment factors)

   DNEL dermal = 2500 mg/kg/day / (4 * 3 * 2)

   DNEL dermal = 104.15 mg/kg/day

 

INHALATION

   Dose descriptor = NOAEL of 250 mg/kg/day; from a well described 13-week oral subchronic repeat dose study.

 

- Route-to-route extrapolation (calculation B.3 in ECHA Guidance R.8)

  inhalatory NOAEC = oral NOAEL * (1/ sRV rat 8h) * (ABS oral / ABS inh) * (sRV human / wRV)

  inhalatory NOAEC= 250 * (1/0.38) * (100/100) * (6.7/10)

  inhalatory NOAEC = 440.79 mg/m3

 

- Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rat

2.5

Intraspecies - workers

3

Subchronic study to Chronic

2

Overall Adjustment Factor

15

-  DNEL calculation

   DNEL inhalation = inhalation NOAEC / (adjustment factors)

   DNEL inhalation = 440.79 mg/m3 / (15)

   DNEL inhalation = 29.39 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.7 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
62.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The REACH Technical Guidance Document R.8 contains default assessment factors which should be applied to a modified dose descriptor in order to obtain a DNEL. These factors are multiplicative and can lead to a human chronic NAEL that is 100 or 200 fold lower than the equivalent rat subchronic NOAEL. However other guidance is available from ECETOC (2003), which supports smaller assessment factors to account for inter- and intra- species differences; leading to a human chronic NAEL that is only 24 to 40 -fold lower than an equivalent rat sub\chronic NOAEL. The ECETOC technical report includes scientific justification for the magnitude of these assessment factors, including:

· Although “residual” interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability.

· Following analysis of the inherent variability in human toxicokinetic and toxicodynamic parameters, a difference of 3 (close to the 90th percentile) was considered appropriate to account for variability present in worker groups while a value of 5 (equivalent to the 95th percentile) was appropriate for the general population.

Section R.8.4.3.3 of the REACH Technical Guidance Document recognizes that the overall assessment factor applied to an experimental NOAEL when developing a DNEL is multiplicative in nature, and that “Care should be taken to avoid double counting several aspects when multiplying the individual factors.” Based on the information presented in ECETOC (2003) and summarized above, use of the standard defaults for inter- and intra- species variability contained in REACH Technical Guidance Document appears to result in “double counting”, and if used inappropriately, would lead to a large, conservative overall assessment factor. In order to retain the scientific credibility in its DNEL setting process, we will adopt the assessment factors proposed by ECETOC (2003) when developing DNELs.

 

Critical NOAEL used = rabbit oral NOAEL 250 mg/kg/day (13-week oral subchronic repeat dose study – systemic)

Absorption rates: 10% dermal, 100% oral, and 100% inhalation regardless of species

Dermal - Systemic

Dose descriptor = NOAEL of 250 mg/kg/day; from a well described 13-week oral subchronic repeat dose study.

 

Modification of dose descriptor

= dermal NOAEL * (rat oral absorption rate / human dermal absorption rate)

= 250 * (100% / 10%)

dermal NOAEL = 2500 mg/kg/day

 

Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rat

4

Intraspecies – general population

5

Subchronic study to Chronic       

2

Overall Adjustment Factor

40

 

DNEL calculation

DNEL dermal = dermal NOAEL / (adjustment factors)

DNEL dermal = 2500 mg/kg/day / (4 * 5 * 2)

DNEL dermal = 62.50 mg/kg/day

 

 

Inhalation

Dose descriptor = NOAEL of 250 mg/kg/day; from a well described 13-week oral subchronic repeat dose study.

 

Route-to-route extrapolation (calculation B.3 in ECHA Guidance R.8)

inhalatory NOAEC = oral NOAEL * (1/ sRV rat 24h) * (ABS oral / ABS inh)

inhalatory NOAEC= 250 * (1/1.15) * (100/100)

inhalatory NOAEC = 217.39 mg/m3

 

Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rat

2.5

Intraspecies – General Population

5

Subchronic study to Chronic    

2

Overall Adjustment Factor

25

 

DNEL calculation

DNEL inhalation = inhalation NOAEC / (adjustment factors)

DNEL inhalation = 217.39 mg/m3 / (25)

DNEL inhalation = 8.70 mg/m3

 

Oral

Dose descriptor = NOAEL of 250 mg/kg/day; from a well described oral development toxicity study

 

Modification of dose descriptor: Not required

 

Adjustment factors (ECETOC Technical Report #86):

Criteria

Adjustment Factor

Allometric scaling - rat

4

Intraspecies – General Population

5

Subchronic study to Chronic    

2

Overall Adjustment Factor

40

 

DNEL calculation

DNEL oral = oral NOAEL / (adjustment factors)

DNEL oral = 250 mg/kg/day / (40)

DNEL oral = 6.25 mg/kg/day