Mixed LOF

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 800 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Boogaard PJ, et al. A consistent and transparent approach for calculation of Derived No-Effect Levels (DNELs) for petroleum substances. Regul Toxicol Pharmacol. 2012 Feb;62(1):85-98

Overall assessment factor (AF):

3

Modified dose descriptor starting point:

LOAEC

Value:

11 578 mg/m³

Explanation for the modification of the dose descriptor starting point:

Drinker 1943. Basis is Lowest Observed Effective Concentration of 4320 mg/m3 causing central nervous system effects in human volunteers following 1 hour of inhalation of gasoline vapor (primarily C4-C6). , adjusted for a 15 minute exposure duration (60 min / 15 min = 4) and ventilation rate (6.7 m3 for person at rest / 10 m3 for worker = 0.67), for a calculated adjusted LOAEC of 11578 mg/m3.

AF for dose response relationship:

3

Justification:

Use of a LOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Unecessary because human data used

AF for other interspecies differences:

1

Justification:

Unecessary because human data used

AF for intraspecies differences:

1

Justification:

Boogaard 2012. “The CNS effects [narcosis] caused by petroleum hydrocarbons are due to membrane changes, which are caused by the dissolution of the hydrocarbons in the phospholipid bilayer (Sikkema et al., 1995). This effect is driven by physico-chemical properties, like the value for log Pow of the substance; hence CNS depression is not expected to differ among species since the phospholipid bilayer is essentially identical in mammalian species (Baker et al., 1985; Hissink et al., 2007; Shugaev, 1969). For this reason the default AF of 2.5 as suggested by ECHA, to account for toxicodynamic differences between species, is substituted by an IAF of 1 for petroleum hydrocarbons. Differences in toxicokinetics, such as those caused by differences in solubility in the blood which are largely determined by physico-chemical properties, are also considered to be minimal.”

AF for the quality of the whole database:

1

Justification:

Database covers all information requirements

AF for remaining uncertainties:

1

Justification:

None identified

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 100 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: Boogaard PJ, et al. A consistent and transparent approach for calculation of Derived No-Effect Levels (DNELs) for petroleum substances. Regul Toxicol Pharmacol. 2012 Feb;62(1):85-98

Overall assessment factor (AF):

9

Dose descriptor:

LOAEC

Value:

2 400 mg/m³

AF for dose response relationship:

3

Justification:

Drinker 1943. A Lowest Observed Adverse Effective Concentration of 2400 mg/m3 caused minor eye irritation in 2 out of 9 human volunteers following 1 hour of inhalation of vapor (primarily C4-C6). An adjusted LOAEC was derived by multiplying by 4 (60 min/15 min = 4), resulting in an adjusted LOAEC of 9600 mg/m3. The application of a total adjustment factor of 9 results in a NOEC = 1070 mg/m3 (rounded to 1100 mg/m3).

AF for differences in duration of exposure:

1

Justification:

Point of departure is experimental data from human volunteers and 1 hour of exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Human volunteers and no species adjustment necessary

AF for other interspecies differences:

1

Justification:

Human volunteers and no species adjustment necessary.

AF for intraspecies differences:

3

Justification:

Upper 95th percentile estimates of variability based on toxico-kinetic and -dynamic factors from databases considering a both sexes and range of ages and disease states are 4.3 to 3.8. As such, an assessment factor of 3 was considered sufficiently conservative for application to the worker population assessment for both toxicokinetics and toxicodynamics (ECETOC, "Guidance on Assessment Factors to Derive a DNEL." Technical Report 110, 2010).

AF for the quality of the whole database:

1

Justification:

Database covers all information requirements

AF for remaining uncertainties:

1

Justification:

None identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3 800 mg/m³

Most sensitive endpoint:

neurotoxicity

DNEL related information

DNEL derivation method:

other: Boogaard PJ, et al. A consistent and transparent approach for calculation of Derived No-Effect Levels (DNELs) for petroleum substances. Regul Toxicol Pharmacol. 2012 Feb;62(1):85-98

Overall assessment factor (AF):

3

Dose descriptor starting point:

LOAEC

Value:

2 400 mg/m³

AF for dose response relationship:

3

Justification:

LOAEC to NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Human Volunteer information. Not Necessary.

AF for other interspecies differences:

1

Justification:

Boogaard 2012. “The CNS effects [narcosis] caused by petroleum hydrocarbons are due to membrane changes, which are caused by the dissolution of the hydrocarbons in the phospholipid bilayer (Sikkema et al., 1995). This effect is driven by physico-chemical properties, like the value for log Pow of the substance; hence CNS depression is not expected to differ among species since the phospholipid bilayer is essentially identical in mammalian species (Baker et al., 1985; Hissink et al., 2007; Shugaev, 1969). For this reason the default AF of 2.5 as suggested by ECHA, to account for toxicodynamic differences between species, is substituted by an IAF of 1 for petroleum hydrocarbons. Differences in toxicokinetics, such as those caused by differences in solubility in the blood which are largely determined by physico-chemical properties, are also considered to be minimal.”

AF for intraspecies differences:

1

Justification:

see Boogaard 2012.

AF for the quality of the whole database:

1

Justification:

Key study is supported by additional studies and PBPK information.

AF for remaining uncertainties:

1

Justification:

All endpoints covered by data

Workers - 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:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 960 mg/m³

Most sensitive endpoint:

neurotoxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: Boogaard PJ, et al. A consistent and transparent approach for calculation of Derived No-Effect Levels (DNELs) for petroleum substances. Regul Toxicol Pharmacol. 2012 Feb;62(1):85-98

Overall assessment factor (AF):

3

Dose descriptor starting point:

LOAEC

Value:

4 320

Modified dose descriptor starting point:

LOAEC

Value:

5 875 mg/m³

Explanation for the modification of the dose descriptor starting point:

Basis is Lowest Observed Effective Concentration of 4320 mg/m3 causing central nervous system effects in human volunteers following 1 hour of inhalation of gasoline vapor (primarily C4-C6). , adjusted for a 15 minute exposure duration (60 min / 15 min = 4) and ventilation rate (6.7 m3 for person at rest / 20 m3 for general population = 0.34), for a calculated adjusted LOAEC of 5875 mg/m3.

AF for dose response relationship:

3

Justification:

Use of a LOAEL and observed effect (onset of neuromuscular symptoms) is not severe

AF for interspecies differences (allometric scaling):

1

Justification:

Not necessary because data is from humans

AF for other interspecies differences:

1

Justification:

Not necessary because data is from humans

AF for intraspecies differences:

1

Justification:

Boogaard 2012. “The CNS effects [narcosis] caused by petroleum hydrocarbons are due to membrane changes, which are caused by the dissolution of the hydrocarbons in the phospholipid bilayer (Sikkema et al., 1995). This effect is driven by physico-chemical properties, like the value for log Pow of the substance; hence CNS depression is not expected to differ among species since the phospholipid bilayer is essentially identical in mammalian species (Baker et al., 1985; Hissink et al., 2007; Shugaev, 1969). For this reason the default AF of 2.5 as suggested by ECHA, to account for toxicodynamic differences between species, is substituted by an IAF of 1 for petroleum hydrocarbons. Differences in toxicokinetics, such as those caused by differences in solubility in the blood which are largely determined by physico-chemical properties, are also considered to be minimal.”

AF for the quality of the whole database:

1

Justification:

Database covers all information requirements

AF for remaining uncertainties:

1

Justification:

None identified as necessary

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

640 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: Boogaard PJ, et al. A consistent and transparent approach for calculation of Derived No-Effect Levels (DNELs) for petroleum substances. Regul Toxicol Pharmacol. 2012 Feb;62(1):85-98

Overall assessment factor (AF):

15

Dose descriptor:

LOAEC

Value:

2 400 mg/m³

AF for dose response relationship:

3

Justification:

LOAEC adjusted to NOAEC

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

Justification:

Data is from human volunteers.

AF for other interspecies differences:

1

Justification:

Human volunteer data.

AF for intraspecies differences:

5

Justification:

Upper 95th percentile estimates of variability based on toxico-kinetic and -dynamic factors from databases considering a both sexes and range of ages and disease states are 4.3 to 3.8. As such, an assessment factor of 5 was considered sufficiently conservative for application to general population assessment (ECETOC, "Guidance on Assessment Factors to Derive a DNEL." Technical Report 110, 2010).

AF for the quality of the whole database:

1

Justification:

Database covers all information requirements

AF for remaining uncertainties:

1

Justification:

None identified as necessary

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 960 mg/m³

Most sensitive endpoint:

neurotoxicity

DNEL related information

DNEL derivation method:

other: Boogaard PJ, et al. A consistent and transparent approach for calculation of Derived No-Effect Levels (DNELs) for petroleum substances. Regul Toxicol Pharmacol. 2012 Feb;62(1):85-98

Overall assessment factor (AF):

3

Dose descriptor starting point:

LOAEC

Value:

4 320 mg/m³

AF for dose response relationship:

3

Justification:

Drinker 1943. Basis is Lowest Observed Effective Concentration of 4320 mg/m3 causing central nervous system effects in human volunteers following 1 hour of inhalation of gasoline vapor (primarily C4-C6). , adjusted for a 15 minute exposure duration (60 min / 15 min = 4) and ventilation rate (6.7 m3 for person at rest / 20 m3 for general population = 0.34), for a calculated adjusted LOAEC of 5875 mg/m3. A value of 1958 mg/m3 was calculated by dividing the adjusted LOAEC by an assessment factor (AF) of 3 (LOAEC to NOAEC), then rounded to 1960 mg/m3 for a DNEL. No additional AFs are necessary for narcosis (Boogaard 2012).

AF for interspecies differences (allometric scaling):

1

Justification:

Data is derived from human volunteer data and inhalation data is already considered to be allometrically scaled.

AF for other interspecies differences:

1

Justification:

Data is derived from human volunteer data.

AF for intraspecies differences:

1

Justification:

Boogaard 2012. “The CNS effects [narcosis] caused by petroleum hydrocarbons are due to membrane changes, which are caused by the dissolution of the hydrocarbons in the phospholipid bilayer (Sikkema et al., 1995). This effect is driven by physico-chemical properties, like the value for log Pow of the substance; hence CNS depression is not expected to differ among species since the phospholipid bilayer is essentially identical in mammalian species (Baker et al., 1985; Hissink et al., 2007; Shugaev, 1969). For this reason the default AF of 2.5 as suggested by ECHA, to account for toxicodynamic differences between species, is substituted by an IAF of 1 for petroleum hydrocarbons. Differences in toxicokinetics, such as those caused by differences in solubility in the blood which are largely determined by physico-chemical properties, are also considered to be minimal.”

AF for the quality of the whole database:

1

Justification:

Data and supporting studies cover the relevant endpoint.

AF for remaining uncertainties:

1

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:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)