Heptanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol pentanoate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

34 mg/m³

Most sensitive endpoint:

repeated dose toxicity

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:

2 557 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose the default respiratory volume for the rat corresponding to the daily duration of human exposure is considered in the first step, followed by a correction for the difference between respiratory rates of workers under standard conditions and under light activity in the second step. NAECcorr_inh = oral NOAEL (1450) x 1/0.38 m3/kg bw x 6.7 m3/10 m3 = 2557 mg/m3. As a worst case, oral absorption in rats in humans is assumed to be 100% and inhalation absorption in humans is assumed to be 100%. Therefore, correction factor for differences in the rates of absorption for the oral and the inhalation routes in rats and humans is: ABS rat-oral/ABS human-inhalation = 100/100 = 1. Therefore, NAECcorr_inh = 2557 x 1 = 2557 mg/m3.

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling required for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

5

Justification:

Default assessment factor of 5 for workers

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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:

4.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

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:

1 450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Assume that oral absorption in rats is 100% and that dermal absorption in humans is 100%. Therefore dose descriptor after route to route extrapolation is 1450 x 100/100 = 1450 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rat = 4

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

5

Justification:

Default assessment factor of 5 for workers

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 mg/cm²

Most sensitive endpoint:

developmental toxicity / teratogenicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for differences in duration of exposure:

1

Justification:

Local effect

AF for interspecies differences (allometric scaling):

1

Justification:

Local effect

AF for other interspecies differences:

1

Justification:

Likely to be a direct effect

AF for intraspecies differences:

5

Justification:

Default assessment factor of 5 for workers

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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

There is one 28 day repeated dose oral toxicity study available aimed to characterise the potential toxic effects of read-across substance, fatty acids, C5-10, esters with pentaerythritol. A NOAEL of 1450 mg/kg bw/day was established for female rats based on the lack of toxicologically relevant effects at the highest dose tested and was selected as starting point for deriving the long-term systemic inhalation DNEL and the long-term systemic dermal DNEL. A long-term local dermal DNEL was derived based on local NOAEL of 5.7 mg/cm2 from the prenatal developmental toxicity study. Acute local DNELs (dermal and inhalation) were not derived as the substance is not classified for acute local effects. Acute systemic DNELs (dermal and inhalation) and a long-term local inhalation DNEL were not derived because the substance is not classified for acute effects and there are no data on long-term local effects of inhalation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

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

Value:

1 261 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose, the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hrs exposure of general public). NAECcorr_inh = oral NOAEL (1450) x 1/1.15 m3/kg bw = 1261 mg/m3. As a worst case, oral absorption in rats in humans is assumed to be 100% and inhalation absorption in humans is assumed to be 100%. Therefore, correction factor for differences in the rates of absorption for the oral and the inhalation routes in rats and humans is: ABS rat-oral/ABS human-inhalation = 100/100 = 1. Therefore, NAECcorr_inh = 1261 x 1 = 1261 mg/m3.

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling required for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

10

Justification:

Default assessment factor of 10 for general population

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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:

2.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Assume that oral absorption in rats is 100% and that dermal absorption in humans is 100%. Therefore dose descriptor after route to route extrapolation is 1450 x 100/100 = 1450 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Allometric scaling factor for rat = 4

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

10

Justification:

Default assessment factor for general population

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.57 mg/cm²

Most sensitive endpoint:

developmental toxicity / teratogenicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

other: NOAEL

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health).

AF for differences in duration of exposure:

1

Justification:

Local effect

AF for interspecies differences (allometric scaling):

1

Justification:

Local effect

AF for other interspecies differences:

1

Justification:

Likely to be a direct effect

AF for intraspecies differences:

10

Justification:

Default assessment factor for the general population

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

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:

2.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

1 450 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not required

AF for dose response relationship:

1

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC

AF for differences in duration of exposure:

6

Justification:

Default assessment factor for extrapolation from subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

Factor for allometric scaling for rat

AF for other interspecies differences:

2.5

Justification:

Default assessment factor

AF for intraspecies differences:

10

Justification:

Default assessment factor for general population

AF for the quality of the whole database:

1

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

AF for remaining uncertainties:

1

Justification:

It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

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

There is one 28 day repeated dose oral toxicity study available aimed to characterise the potential toxic effects of read-across substance, fatty acids, C5-10, esters with pentaerythritol. A NOAEL of 1450 mg/kg bw/day was established for female rats based on the lack of toxicologically relevant effects at the highest dose tested and was selected as starting point for deriving the long-term systemic inhalation DNEL, the long-term systemic dermal DNEL and the long-term systemic oral DNEL. A long-term local dermal DNEL was derived based on local NOAEL of 5.7 mg/cm2 from the prenatal developmental toxicity study. Acute local DNELs (dermal and inhalation) were not derived as the substance is not classified for acute local effects. Acute systemic DNELs (dermal and inhalation) and a long-term local inhalation DNEL were not derived because the substance is not classified for acute effects and there are no data on long-term local effects of inhalation.