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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:
2.94 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEC
DNEL value:
220.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
ECHA REACH Guidance, Chapter R.8, Example B.3
AF for dose response relationship:
3
Justification:
Default from Guidance for LOAEL to NOAEL extrapolation
AF for differences in duration of exposure:
2
Justification:
Default from Guidance for sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Default from Guidance for the rat
AF for other interspecies differences:
2.5
Justification:
Default from Guidance
AF for intraspecies differences:
5
Justification:
Default from Guidance
AF for the quality of the whole database:
1
Justification:
Default from Guidance
AF for remaining uncertainties:
1
Justification:
Default from Guidance
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:
0.83 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
DNEL value:
250 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
ECHA REACH Guidance, Chapter R.8, Example B.5
AF for dose response relationship:
3
Justification:
Default from Guidance for LOAEL to NOAEL extrapolation
AF for differences in duration of exposure:
2
Justification:
Default from Guidance for sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
Default from Guidance for the rat
AF for other interspecies differences:
2.5
Justification:
Default from Guidance
AF for intraspecies differences:
5
Justification:
Default from Guidance for Workers
AF for the quality of the whole database:
1
Justification:
Default from Guidance
AF for remaining uncertainties:
1
Justification:
Default from Guidance
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Introduction

DNELs have been developed for diisobutyl phthalate (DIBP) in order to determine whether adequate control is demonstrated for the endpoint(s) of concern that led to its inclusion in Annex XIV. Hence the DNELs developed below focus primarily on effects on the reproductive system and development. However since repeated exposure to DIBP has also been shown to cause adverse effects in the liver of rodents, comparative DNELs were derived also for this endpoint.

Toxicokinetics

Information available for the related substances DPB and DEHP indicates rapid uptake and excretion following oral administration. Therefore for the purposes of risk characterisation of DIBP, 100% absorption will be assumed for human oral exposure. For dermal absorption, information indicating excretion of approximately 60% of an applied dose of DIBP by rat skin together with other findings suggesting that human skin is less permeable to phthalate diesters than is rat skin leads to a conservative estimate of 50% uptake of DIBP by human skin. Limited information for the related substance DEHP indicates lung absorption of around 75%. For the purposes of risk characterisation of DIBP, 100% absorption will be assumed for human inhalation exposure.

Acute toxicity

A DNEL for acute toxicity should be derived if an acute hazard leading to acute toxicity (e.g. classified under DSD) has been identified and there is a potential for high peak exposures. If no hazard has been identified then a DNEL for acute toxicity is unnecessary as the long-term DNEL will be sufficient to ensure that adverse effects do no occur. DIBP is neither acutely toxic nor is it an irritant (eye, skin or respiratory tract) and therefore no acute DNELs (systemic or local) have been calculated.

Long-term systemic toxicity

The available data indicate a NOAEL of 70 mg/kg bw/d for DIBP, based on body weight effects in the rat following oral gavage administration for 4 months (Hodge, 1954). Higher exposures are associated with changes in the (male) reproductive system while information for the the homologues DBP indicates that the liver (peroxysome proliferation) is another target tissue in the rat.

Inhalation DNEL (systemic)

Dose descriptor

The rat 4-mo oral NOAEL of 70 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent rat inhalation NOAEC will be derived using route-to-route extrapolation, based on 100% absorption after ingestion and inhalation.

The inhalatory NOAEC may be calculated as follows:

NOAECinhalation = NOAELoral x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRVhuman

= 70 x 1/0.38 x 100/100 x 6.7/10

= 123.4 mg/m3 (4-mo duration of exposure)

Assessment factors

Uncertainty

AF

Interspecies differences

1

Remaining interspecies differences

2.5

Intraspecies differences

5

Differences in duration of exposure

2

Dose response and endpoint specific/severity issues

1

Quality of database

1

 

 

Overall AF

25

 

DNELl-t inhal-systemic = 123.4 / 25 = 4.94 mg/m3

Dermal DNEL (systemic)

Dose descriptor

The rat 4-mo oral NOAEL of 70 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent dermal NOAEL will be derived using route-to-route extrapolation, based on 100% absorption after ingestion and 50% after skin contact.

The dermal NOAEL may be calculated as follows:

NOAELdermal = NOAELoral x ABSoral-rat/ABSdermal-human

= 70 x 100/50

= 140 mg/kg bwt/d (4-mo duration of exposure)

Assessment factors

Uncertainty

AF

Interspecies differences

4

Remaining interspecies differences

2.5

Intraspecies differences

5

Differences in duration of exposure

2

Dose response and endpoint specific/severity issues

1

Quality of database

1

 

 

Overall AF

100

 

DNELl-t dermal-systemic = 140 / 100 = 1.40 mg/kg bw/d

Long-term reproductive toxicity

The male reproductive system is a probable target following pre-natal and post-natal exposure to DIBP, with a LOAEL of 125 mg DIBP/kg bw/d (Saillenfait et al., 2008). Changes in foetal testicular testosterone production together with an increased incidence of malformations and variations (including undescended testes and altered transabdominal testicular migration) apparent at higher exposures. A DNEL based upon a LOAEL of 125 mg/kg bw/d is considered adequately protective against possible effects on fertility and foetal development.

Inhalation DNEL (fertility and development)

Dose descriptor

The rat pre-natal/post-natal LOAEL of 125 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent rat inhalation LOAEC will be derived using route-to-route extrapolation, based on 100% absorption after ingestion and inhalation.

The inhalatory LOAEC may be calculated as follows:

LOAECinhalation = LOAELoral x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRVhuman

= 125 x 1/0.38 x 100/100 x 6.7/10

= 220.4 mg/m3

Assessment factors

Uncertainty

AF

Interspecies differences

1

Remaining interspecies differences

2.5

Intraspecies differences

5

Differences in duration of exposure

2

Dose response and endpoint specific/severity issues (LOAEL to NOAEL)

3

Quality of database

1

 

 

Overall AF

75

 

DNELl-t inhalation-repro = 220.4 / 75 = 2 94 mg/m3

Dermal DNEL (fertility and development)

Dose descriptor

The rat pre-natal/post-natal LOAEL of 125 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent dermal LOAEL will be derived using route-to-route extrapolation, based on 100% absorption after ingestion and 50% after skin contact.

The dermal LOAEL may be calculated as follows:

LOAELdermal = LOAELoral x ABSoral-rat/ABSdermal-human

= 125 x 100/50

= 250 mg/kg bwt/d

Assessment factors

Uncertainty

AF

Interspecies differences

4

Remaining interspecies differences

2.5

Intraspecies differences

5

Differences in duration of exposure

2

Dose response and endpoint specific/severity issues (LOAEL to NOAEL)

3

Quality of database

1

 

 

Overall AF

300

 

DNELl-t dermal-repro = 250 / 300 = 0.83 mg/kg bw/d

Conclusion

For DIBP, the DNELs derived for toxicity to reproduction are lower than the DNELs derived for repeated dose toxicity. The former will therefore be used for risk characterisation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.72 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Modified dose descriptor starting point:
NOAEC
DNEL value:
108.7 mg/m³
Explanation for the modification of the dose descriptor starting point:
ECHA REACH Guidance, Chapter R.8, Example R.8-1
AF for dose response relationship:
3
Justification:
Default from Guidance for LOAEL to NOAEL extrapolation
AF for differences in duration of exposure:
2
Justification:
Default from Guidance for sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
1
Justification:
Default from Guidance for the rat
AF for other interspecies differences:
2.5
Justification:
Default from Guidance
AF for intraspecies differences:
10
Justification:
Default from Guidance
AF for the quality of the whole database:
1
Justification:
Default from Guidance
AF for remaining uncertainties:
1
Justification:
Default from Guidance
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:
no hazard identified
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:
0.21 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
LOAEL
DNEL value:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route-to-route extrapolation necessary
AF for dose response relationship:
3
Justification:
Default from Guidance for LOAEL to NOAEL extrapolation
AF for differences in duration of exposure:
2
Justification:
Default from Guidance for sub-chronic to chronic extrapolation
AF for interspecies differences (allometric scaling):
4
Justification:
Default from Guidance for the rat
AF for other interspecies differences:
2.5
Justification:
Default from Guidance
AF for intraspecies differences:
10
Justification:
Default from Guidance
AF for the quality of the whole database:
1
Justification:
Default from Guidance
AF for remaining uncertainties:
1
Justification:
Default from Guidance
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

Introduction

Long-term DNELs have been developed for diisobutyl phthalate (DIBP) in order to characterise risks associated with environmental exposures (“man via the environment”). These DNELs for the inhalation and oral routes of exposure focus on effects on the reproductive system and development since, as discussed in the Worker section, the results will protect also against systemic effects.

Toxicokinetics

Information available for the related substances DPB and DEHP indicates rapid uptake and excretion following oral administration. Therefore for the purposes of risk characterisation of DIBP, 100% absorption will be assumed for human oral exposure. Limited information for the related substance DEHP indicates lung absorption of around 75%. For the purposes of risk characterisation of DIBP, 100% absorption will be assumed for human inhalation exposure.

Long-term toxicity

The male reproductive system is a probable target following pre-natal and post-natal exposure to DIBP, with a LOAEL of 125 mg DIBP/kg bw/d (Saillenfait et al., 2008). Changes in foetal testicular testosterone production together with an increased incidence of malformations and variations (including undescended testes and altered transabdominal testicular migration) apparent at higher exposures. A DNEL based upon a LOAEL of 125 mg/kg bw/d is considered adequately protective against possible effects on fertility and foetal development.

Inhalation DNEL (fertility and development)

Dose descriptor

The rat pre-natal/post-natal LOAEL of 125 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

The equivalent rat inhalation LOAEC will be derived using route-to-route extrapolation, based on 100% absorption after ingestion and inhalation.

The inhalatory LOAEC may be calculated as follows:

LOAECinhalation = LOAELoral x 1/sRVrat(24hr) x ABSoral-rat/ABSinh-human

= 125 x 1/1.15 x 100/100

= 108.7 mg/m3

Assessment factors

Uncertainty

AF

Interspecies differences

1

Remaining interspecies differences

2.5

Intraspecies differences

10

Differences in duration of exposure

2

Dose response and endpoint specific/severity issues (LOAEL to NOAEL)

3

Quality of database

1

 

 

Overall AF

150

  

DNELl-t inhalation-repro = 108.7 / 150 = 0.72 mg/m3

Oral DNEL (fertility and development)

Dose descriptor

The rat pre-natal/post-natal LOAEL of 125 mg/kg bw/d will be used as the starting point.

Modification of dose descriptor

No modification is necessary for frequency of exposure, since animals from the study conducted by Saillenfait et al. (2008) received daily treatments with DIBP which mimics human environmental exposure. Absorption of 100% DIBP after ingestion has been assumed for both rodents and humans.

Assessment factors

Uncertainty

AF

Interspecies differences

4

Remaining interspecies differences

2.5

Intraspecies differences

10

Differences in duration of exposure

2

Dose response and endpoint specific/severity issues (LOAEL to NOAEL)

3

Quality of database

1

 

 

Overall AF

600

  

DNELl-t oral-repro = 125 / 600 = 0.21 mg/kg bw/d