Dibutyl phthalate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 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):

37.5

Modified dose descriptor starting point:

NOAEC

Value:

4.94 mg/m³

Explanation for the modification of the dose descriptor starting point:

Corr inhal NOAEC=2 mg/kg bw/day x (1 / 0.38 m3/kg/day) x (100% / 100%) x (6.7 m3 / 10 m3) = 3.53; 3.53 x (7/5) = 4.94 mg/m3

AF for dose response relationship:

3

Justification:

Since for Dibutyl phthalate, LOAEL, not NOAEL was used in Reproductive toxicity DNEL derivation, AF of 3 was applied.

AF for differences in duration of exposure:

1

Justification:

Regarding Reproduction toxicity, LOAEL was based on developmental study, hence an assessment factor of 1 was introduced.

Justification:

not applied

AF for other interspecies differences:

2.5

Justification:

For inhalatory NOAEC, differences in metabolic rate were already taken into consideration during modification of the NOAEC to the correct starting point. Hence, additional factor of 2.5 for remaining interspecies differences was considered for interspecies differences only.

AF for intraspecies differences:

5

Justification:

For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population. For workers, a default assessment factor of 5 was used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

An assessment factor on the quality of the whole database should - if justified - compensate for the potential remaining uncertainties in the derived DNEL. Based on the fact that the available information met the tonnage driven data requirements necessary to fulfil the REACH requirements, for Dibutyl phthalate, AF = 1 was used.

Justification:

not applied

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.84 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

DNEL extrapolated from long term DNEL

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:

0.19 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):

150

Modified dose descriptor starting point:

NOAEL

Value:

28 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

10x oral NOAELrat = corrected dermal NOAELhuman = 20 mg/kg bw/day. Next, correction for the 5-day exposure a week (workers conditions), instead of 7-day exposure a week (experimental conditions) was performed: 20mg/kg bw/day x (7/5) = 28 mg/kg bw/day. (and further assessment factors, incl. allometric scaling from rat to human were applied)

AF for dose response relationship:

3

Justification:

Since for Dibutyl phthalate, extrapolation from LOAEL to NOAEL was used in Reproductive toxicity DNEL derivation, AF of 3 was applied.

AF for differences in duration of exposure:

1

Justification:

Regarding Reproduction toxicity, LOAEL was based on developmental study, hence an assessment factor of 1 was introduced.

AF for interspecies differences (allometric scaling):

4

Justification:

For Dibutyl phthalate, a default factor of 4 for allometric scaling from rat to human was used for dermal NOAEL..

AF for other interspecies differences:

2.5

Justification:

Factor 2.5 is a default factor for interspecies differences remaining after application of allometric scaling (where applicable).

AF for intraspecies differences:

5

Justification:

For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population. For workers, a default assessment factor of 5 was used, based on the fact that this sub population does not cover the very young, the very old, and the very ill.

AF for the quality of the whole database:

1

Justification:

Since dermal absorption of DBP was 10% of oral absorption, assessment factor of 1 was used for the Quality of the database, despite the fact that oral-to-dermal extrapolation was performed (Guidance on information requirements and chemical safety assessment Chapter R.8, ECHA 2012)

Justification:

not applies

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

Risk assessment of Dibutylphthalate was performed, reproductive and developmental toxicity being the major health effects considered.

In the risk assessment, the LOAEL of 2 mg/kg bw was used, based on anti-androgenic effects in rats in a developmental toxicity study with exposure during the period from late gestation (Gestational day 15) to the end of lactation on the postnatal day 21 (Lee et al., 2004). The main health outcomes observed were reduced spermatocyte development in prepubertal rats and mammary gland changes in adult male rats. The selected LOAEL is consistent with the EFSA opinion from 2005, with the Proposal for a Restriction by Danish Competent Authority for REACH and Danish Environmental Protection Agency (2011) and with the ECHA RAC/24/2013/09_rev 2. Furthermore, in 2005, EFSA has chosen to change the Tolerable Daily Intake (TDI) in favor of the study by Lee et al. (2004) to 0.01 mg/kg bw/day for DBP based on delayed germ cell development and male mammary gland changes.The LOAEL of 2 mg/kg bw/day from the developmental toxicity study is regarded as the most critical LOAEL (Proposal for a Restriction, 2011; ECHA RAC/24/2013/09_rev 2).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 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

Value:

1.74 mg/m³

Explanation for the modification of the dose descriptor starting point:

Corrected inhalatory NOAEC = 2 mg/kg bw/day x (1 / 1.15 m3/kg/day) x (100% / 100%) = 1.74 mg/m3

AF for dose response relationship:

3

Justification:

Since for Dibutyl phthalate, extrapolation from LOAEL to NOAEL was used in Reproductive toxicity DNEL derivation, AF of 3 was applied (Proposal of a Restriction, 2011; ECHA RAC/24/2013/09_rev 2).

AF for differences in duration of exposure:

1

Justification:

Regarding Reproduction toxicity, LOAEL was based on developmental study, hence an assessment factor of 1 was introduced (Proposal of a Restriction, 2011; ECHA RAC/24/2013/09_rev 2).

Justification:

not applied

AF for other interspecies differences:

2.5

Justification:

For inhalatory NOAEC, differences in metabolic rate were already taken into consideration during modification of the NOAEC to the correct starting point. Hence, additional factor of 2.5 for remaining interspecies differences was considered for interspecies differences only.

AF for intraspecies differences:

10

Justification:

For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population.

AF for the quality of the whole database:

1

Justification:

An assessment factor on the quality of the whole database should - if justified - compensate for the potential remaining uncertainties in the derived DNEL. Based on the fact that the available information met the tonnage driven data requirements necessary to fulfil the REACH requirements, for Dibutyl phthalate, AF = 1 was used.

Justification:

not applied

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:

0.07 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

Value:

20 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

10x oral NOAELrat = corrected dermal NOAELhuman = 20 mg/kg bw/day

AF for dose response relationship:

3

Justification:

Since for Dibutyl phthalate, extrapolation from LOAEL to NOAEL was used in Reproductive toxicity DNEL derivation, AF of 3 was applied (Proposal of a Restriction, 2011; ECHA RAC/24/2013/09_rev 2).

AF for differences in duration of exposure:

1

Justification:

Regarding Reproduction toxicity, LOAEL was based on developmental study, hence an assessment factor of 1 was introduced (Proposal of a Restriction, 2011; ECHA RAC/24/2013/09_rev 2).

AF for interspecies differences (allometric scaling):

4

Justification:

For Dibutyl phthalate, a default factor of 4 for allometric scaling from rat to human was used for dermal NOAEL.

AF for other interspecies differences:

2.5

Justification:

Factor 2.5 is a default factor for interspecies differences remaining after application of allometric scaling (where applicable).

AF for intraspecies differences:

10

Justification:

For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population.

AF for the quality of the whole database:

1

Justification:

Since dermal absorption of DBP was 10% of oral absorption, assessment factor of 1 was used for the Quality of the database, despite the fact that oral-to-dermal extrapolation was performed (Guidance on information requirements and chemical safety assessment Chapter R.8, ECHA 2012)

Justification:

not applied

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:

0.007 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

Value:

2 mg/kg bw/day

AF for dose response relationship:

3

Justification:

Since for Dibutyl phthalate, extrapolation from LOAEL to NOAEL was used in Reproductive toxicity DNEL derivation, AF of 3 was applied (Proposal of a Restriction, 2011; ECHA RAC/24/2013/09_rev 2).

AF for differences in duration of exposure:

1

Justification:

Regarding Reproduction toxicity, LOAEL was based on developmental study, hence an assessment factor of 1 was introduced (Proposal of a Restriction, 2011; ECHA RAC/24/2013/09_rev 2).

AF for interspecies differences (allometric scaling):

4

Justification:

For Dibutyl phthalate, a default factor of 4 for allometric scalling from rat to human was used for oral NOAELs.

AF for other interspecies differences:

2.5

Justification:

Factor 2.5 is a default factor for interspecies differences remaining after application of allometric scaling (where applicable).

AF for intraspecies differences:

10

Justification:

For threshold effects, this factor of 10 is the standard procedure, as a default, when assessing exposure to the general population.

AF for the quality of the whole database:

1

Justification:

An assessment factor on the quality of the whole database should - if justified - compensate for the potential remaining uncertainties in the derived DNEL. The evaluation of the total toxicological database should include an assessment whether the available information meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). To account for deficiencies in the available data set and in identifying its magnitude, the assessor should consider both the data lacking and the data available. For Dibutyl phthalate, AF = 1 was used.

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

Risk assessment of Dibutyl phthalate was performed, reproductive and developmental toxicity being the major health effects considered.

In the risk assessment, the LOAEL of 2 mg/kg bw was used, based on anti-androgenic effects in rats in a developmental toxicity study with exposure during the period from late gestation (Gestational day 15) to the end of lactation on the postnatal day 21 (Lee et al., 2004). The main health outcomes observed were reduced spermatocyte development in prepubertal rats and mammary gland changes in adult male rats. The selectedLOAEL is consistent with the EFSA opinion from 2005, with the Proposal for a Restriction by Danish Competent Authority for REACH and Danish Environmental Protection Agency (2011) and with the ECHA RAC, 2013. Furthermore, in 2005, EFSA has chosen to change the Tolerable Daily Intake (TDI) in favor of the study by Lee et al. (2004) to 0.01 mg/kg bw/day for DBP based on delayed germ cell development and male mammary gland changes.The LOAEL of 2 mg/kg bw/day from the developmental toxicity study is regarded as the most critical LOAEL (Proposal for a Restriction, 2011; ECHARAC/24/2013/09_rev 2).