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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.36 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.6 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Long-term toxicity

There is no established IOELV for BBP. The current DNEL is based on a consideration of the potential of BBP to cause long-term systemic effects, both repeated dose toxicity and reproductive (fertility, developmental) toxicity. 

 

DNELs have been calculated both from inhalation and oral dosing.

 

Inhalation DNEL

Dose descriptor 

A 90-day inhalation study in rats (Roloff, 1982) provides an NOAEC of 218 mg/m3(6 hours/day, 5 days/week); relative liver and kidney weights were increased at the higher test concentration of 789 mg/m3(but with no accompanying histopathological findings). The NOAEC from this study will be used to derive the DNELl-t inhalation.

 

Modification of dose descriptor

In line with ECHA TGD (2008) guidance, this NOAEC is corrected by adjusting for activity driven and absorption percentage differences between humans and rats.

 

Correct the NOAEC to adjust for differences in duration in the animal study (6 h) and the worker (8 h) and light work following the TGD Figure R.8-2:

 

correctedNOAEC = 218 mg/m3x [6 h / 8 h] x [6.7 m3/ 10 m3] = 109 mg/m3

 

It is assumed that BBP is similarly and efficiently (100%) absorbed after inhalation by rats and humans (RAR, 2007).

 

Assessment factors

 

Uncertainty

AF

Justification

Interspecies differences

1

 

 

 

 

2.5

Default to account for differences in metabolic rate when doses in an inhalation study are expressed as a concentration

 

To account for other possible inter-species differences (mainly in pharmacodynamics)

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

2

default factor for sub-chronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC, with only minor effects at the test concentration above this

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

25

 

DNELl-t inhal = 109 mg/m3/ 25 = 4.36 mg/m3

 

 

Oral DNELs

For comparative purposes, oral DNELs have been calculated for both repeated dose toxicity and reproductive toxicity.

Repeated dose toxicity

Dose descriptor

The NOAEL from the 14-week rat study (Ford, 1981) of 151 mg/kg bw/day will be used to derive the DNELl-t oral (repeated dose). Pancreatic lesions were evident at the next highest dose (381 mg/kg bw/day).

Assessment factors

 

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL, with only mild or moderate pancreatic lesions at the LOAEL

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

100

 

DNELl-t oral (repeated dose) = 151 / 100 = 1.5 mg/kg bw/day

 

Reproductive toxicity (fertility)

 

Dose descriptor

The NOAEL from the 2-generation rat study (Tyl et al., 2002) of 250 mg/kg bw/day will be used to derive the DNELl-t oral (fertility). In this study, reduced mating and fertility indices were observed in the F1 generation at the next highest dose (750 mg/kg bw/day).

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

1

duration adjustment for developmental endpoint is not appropriate; NOAEL from a 2-gen study

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL, not an exceptional case of serious effects, good GLP study

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

50

 

DNELl-t oral (fertility) = 250 / 50 = 5 mg/kg bw/day

Reproductive toxicity (developmental)

Dose descriptor

The NOAEL from the 2-generation rat study (Tyl et al., 2002) of 50 mg/kg bw/day will be used to derive the DNELl-t oral (developmental). The main effect at the next highest dose of 250 mg/kg bw/day was decreased anogenital distance in male pups, an observational change occurring during their development.

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

1

duration adjustment for developmental endpoint is not appropriate; NOAEL from a 2-gen study

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL for an observational change with no effect on reproductive function, good GLP study

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

50

 

DNELl-t oral (developmental) = 50 / 50 = 1 mg/kg bw/day

Comparison of oral DNELs with inhalation DNEL

The systemic doses produced by the inhalation DNEL and by each of the oral DNELs have been calculated.

 

Systemic dose in humans arising from the inhalation DNEL

In an 8-hour work shift, a 70-kg man will inhale 10 m3of air. If there is 100% pulmonary absorption, the DNELl-t inhalationof 4.36 mg/m3would deliver a systemic dose of 43.6 mg of BBP (10 x 4.36 mg) or 0.62 mg/kg bw/day.

 

Systemic doses in humans arising from the oral DNELs

The long-term oral DNELs based on avoidance of BBP’s repeated dose toxicity and ability to interfere with fertility and development were 1.5, 5 and 1 mg/kg bw/day respectively. Assuming 70% absorption through the gastrointestinal tract, these would be associated with systemic doses of 0.7-3.5 mg/kg bw/day.

 

The systemic dose of 0.7 mg/kg bw/day arising from the lowest oral DNEL from the 2-generation oral rat study (Tyl et al., 2002) is higher than that of 0.62 mg/kg bw/day arising from the inhalation DNEL from the 90-day rat inhalation study (Roloff, 1982). This provides reassurance that the inhalation DNEL will be protective against the systemic reproductive toxic potential of BBP. 

 

 

Dermal DNEL

In the absence of dermal toxicity studies on BBP, there are two possible studies that might be used to derive a dermal DNEL, the 90-day inhalation study of Roloff (1982) and the 2-generation oral study of Tyl et al. (2002).

1. Roloff (1982)

Dose descriptor 

This rat inhalation study provides an NOAEC of 218 mg/m3(6 hours/day, 5 days/week), which needs to be modified to take account of differences in uptake between the inhalation and dermal routes of exposure (TGD, Appendix R.8-2, adaptation of Example B.4).

 

Modification of dose descriptor

The inhalation NOAEC in the rat (in mg/m3) is converted into a dermal NOAEL in the rat (in mg/kg bw/day) by using a default respiratory volume in the rat (sRVrat) and correcting for differences in absorption between the routes (assuming a default inhalation absorption of 100%, and 5% dermal absorption; RAR, 2007).

 

correctedDermal NOAEL = NOAECinhalationx sRVrat (6-h)x [ABSinhal-rat/ABSdermal-human]

                                    = 218 x 0.288 x [100/5] = 1256 mg/kg bw/day

 

Assessment factors

 

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

2

default sub-chronic (90-day) to chronic

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC with only minor effects at the test concentration above this

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

100

 

 

DNELl-t dermal = 1256 mg/kg bw/day / 100 = 12.6 mg/kg bw/day

 

 

2. Tyl et al. (2002)

Dose descriptor 

This 2-generation oral rat study provides an NOAEL for developmental toxicity of 50 mg/kg bw/day, which needs to be modified to take account of differences in uptake between the oral and dermal routes of exposure (TGD, Appendix R.8-2, Example B.5).

 

Modification of dose descriptor

The oral NOAEL is converted into acorrecteddermal NOAEL in the rat by incorporating differences in absorption between the routes (assuming 70% absorption from the gastrointestinal tract and 5% dermal absorption; RAR, 2007).

 

correctedDermal NOAEL = NOAELoralx [ABSoral-rat/ABSdermal-human]

correctedDermal NOAEL = 50 x [70/5] = 700 mg/kg bw/day

 

Assessment factors

 

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

5

default AF for workers

Differences in duration of exposure

1

duration adjustment for developmental endpoint is not appropriate; NOAEL from a 2-gen study

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL for an observational change with no effect on reproductive function, good GLP study

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

50

 

 

DNELl-t dermal = 700 / 50 = 14 mg/kg bw/day

Thus the Roloff 90-day inhalation study provides the lowest dermal DNEL of 12.6 mg/kg bw/day

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.78 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Long-term toxicity

There is no established IOELV for BBP. The current DNEL is based on a consideration of the potential of BBP to cause long-term systemic effects, both repeated dose toxicity and reproductive (fertility, developmental) toxicity. 

 

DNELs have been calculated both from inhalation and oral dosing.

 

Inhalation DNEL

Dose descriptor 

A 90-day inhalation study in rats (Roloff, 1982) provides an NOAEC of 218 mg/m3(6 hours/day, 5 days/week); relative liver and kidney weights were increased at the higher test concentration of 789 mg/m3(but with no accompanying histopathological findings). The NOAEC from this study will be used to derive the DNELl-t inhalation.

 

Modification of dose descriptor

In line with ECHA TGD (2008) guidance, this NOAEC is corrected by adjusting fordifferences in duration in the animal study (6 hours/day, 5 days/week) and the general population (24 hours/day, 7 days/week) following the TGD Figure R.8-2:

 

correctedNOAEC = 218 mg/m3x [6 h / 24 h] x [5 day / 7 day] = 38.9 mg/m3

 

It is assumed that BBP is similarly and efficiently (100%) absorbed after inhalation by rats and humans (RAR, 2007).

 

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

1

 

 

 

2.5

Default to account for differences in metabolic rate when doses in an inhalation study are expressed as a concentration

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

10

default AF for general population

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC, with only minor effects at the test concentration above this

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

50

 

DNELl-t inhalation = 38.9 mg/m3/ 50 = 0.78 mg/m3

 

Oral DNELs

Oral DNELs have been calculated for both repeated dose toxicity and reproductive toxicity.

Repeated dose toxicity

Dose descriptor

The NOAEL from the 14-week rat study (Ford, 1981) of 151 mg/kg bw/day will be used to derive the DNELl-t oral (repeated dose). Pancreatic lesions were evident at the next highest dose (381 mg/kg bw/day).

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

10

default AF for general population

Differences in duration of exposure

2

default factor for subchronic to chronic extrapolation

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL, with only mild or moderate pancreatic lesions at the LOAEL

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

200

 

DNELl-t oral (repeated dose)= 151 / 200 = 0.76 mg/kg bw/day

Reproductive toxicity (fertility)

Dose descriptor

The NOAEL from the 2-generation rat study (Tyl et al., 2002) of 250 mg/kg bw/day will be used to derive the DNELl-t oral (fertility). In this study, reduced mating and fertility indices were observed in the F1 generation at the next highest dose (750 mg/kg bw/day).

Assessment factors

 

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

10

default AF for general population

Differences in duration of exposure

1

duration adjustment for developmental endpoint is not appropriate; NOAEL from a 2-gen study

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL, not an exceptional case of serious effects, good GLP study

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

100

 

DNELl-t oral (fertility) = 250 / 100 = 2.5 mg/kg bw/day

Reproductive toxicity (developmental)

Dose descriptor

The NOAEL from the 2-generation rat study (Tyl et al., 2002) of 50 mg/kg bw/day will be used to derive the DNELl-t oral (developmental). The main effect at the next highest dose of 250 mg/kg bw/day was decreased anogenital distance in male pups, an observational change occurring during their development.

Assessment factors

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

10

default AF for general population

Differences in duration of exposure

1

duration adjustment for developmental endpoint is not appropriate; NOAEL from a 2-gen study

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL for an observational change with no effect on reproductive function, good GLP study

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

100

 

DNELl-t oral (developmental) = 50 / 100 = 0.5 mg/kg bw/day

The developmental effects observed in the Tyl study provide the lowest oral DNEL of 0.5 mg/kg bw/day.

Comparison of oral DNELs with inhalation DNEL

The systemic doses produced by the inhalation DNEL and by each of the oral DNELs have been calculated.

Systemic dose in humans arising from the inhalation DNEL

In a 24-hour day, a 70-kg man will inhale 20 m3of air. If there is 100% pulmonary absorption, the DNELl-t inhalationof 0.78 mg/m3would deliver a systemic dose of 15.6 mg of BBP (20 x 0.78 mg) or 0.22 mg/kg bw/day.

 

Systemic doses in humans arising from the oral DNELs

The long-term oral DNELs based on avoidance of BBP’s repeated dose toxicity and ability to interfere with fertility and development were 0.76, 2.5 and 0.5 mg/kg bw/day respectively. Assuming 70% absorption through the gastrointestinal tract, these would be associated with systemic doses of 0.35-1.8 mg/kg bw/day.

The systemic dose of 0.35 mg/kg bw/day arising from the lowest oral DNEL from the 2-generation oral rat study (Tyl et al., 2002) is

higher than that of 0.22 mg/kg bw/day arising from the inhalation DNEL from the 90-day rat inhalation study (Roloff, 1982). This provides reassurance that the inhalation DNEL will be protective against the reproductive toxic potential of BBP. 

 

 

Dermal DNEL

In the absence of dermal toxicity studies on BBP, there are two possible studies that might be used to derive a dermal DNEL, the 90-day inhalation study of Roloff (1982) and the 2-generation oral study of Tyl et al. (2002).

1. Roloff (1982)

Dose descriptor 

This rat inhalation study provides an NOAEC of 218 mg/m3(6 hours/day, 5 days/week), which needs to be modified to take account of differences in uptake between the inhalation and dermal routes of exposure (TGD, Appendix R.8-2, adaptation of Example B.4).

 

Modification of dose descriptor

The inhalation NOAEC in the rat (in mg/m3) is corrected to adjust for differences in duration of exposure, then converted into a dermal NOAEL in the rat (in mg/kg bw/day) by using a default respiratory volume in the rat (sRVrat) and correcting for differences in absorption between the routes (assuming a default inhalation absorption of 100%, and 5% dermal absorption; RAR, 2007).

 

correctedDermal NOAEL =

                          NOAECinhalationx sRVrat (6 h)x [5 / 7 days] x [ABSinhal-rat/ABSdermal-human]

                                    = 218 x 0.288 x (5/7) x (100/5) = 897 mg/kg bw/day

 

Assessment factors

 

Uncertainty

AF

Justification

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

10

default AF for general population

Differences in duration of exposure

2

default sub-chronic (90-day) to chronic

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEC with only minor effects at the test concentration above this

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

200

 

 

DNELl-t dermal = 897 mg/kg bw/day / 200 = 4.5 mg/kg bw/day

 

 

2. Tyl et al. (2002)

Dose descriptor 

This 2-generation oral rat study provides an NOAEL for developmental toxicity of 50 mg/kg bw/day, which needs to be modified to take account of differences in uptake between the oral and dermal routes of exposure (TGD, Appendix R.8-2, Example B.5).

 

Modification of dose descriptor

The oral NOAEL is converted into acorrecteddermal NOAEL in the rat by incorporating differences in absorption between the routes (assuming 70% absorption from the gastrointestinal tract and 5% dermal absorption; RAR, 2007).

 

correctedDermal NOAEL = NOAELoralx [ABSoral-rat/ABSdermal-human]

correctedDermal NOAEL = 50 x [70/5] = 700 mg/kg bw/day

 

Assessment factors

 

Uncertainty

AF

Justificatio

Interspecies differences

4

 

2.5

Allometric scaling factor for rat

 

To account for other possible interspecies differences (mainly in pharmacodynamics)

Intraspecies differences

10

default AF for general population

Differences in duration of exposure

1

duration adjustment for developmental endpoint is not appropriate; NOAEL from a 2-gen study

Dose response and endpoint specific/severity issues

1

default AF; clear NOAEL for an observational change with no effect on reproductive function, good GLP study

Quality of database

1

default; reliable data available for all REACH required endpoints

Overall AF

100

 

 

DNELl-t dermal = 700 / 100 = 7 mg/kg bw/day

 

Thus the 90-day rat inhalation study of Roloff, 1982 provides the lowest dermal DNEL.