Dodecanedioic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

127 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):

14.2

Dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Starting point

No adverse effects were noted in a 90-day oral gavage study with rats at the highest dose level tested, the NOAEL was exceeding 1800 mg/kg bw/d. This value is taken as starting point to derive a DNEL_{long term.}

Also no adverse effects were noted in a combined reprotoxicity screening and repeated dose study at the highest dose level of 1000 mg/kg bw/day in rats. Dodecanedioic acid was not genotoxic and there was not carcinogenic activity.

 

Route to route extrapolation

Toxicokinetic studies with experimental animals (rats) and human volunteers demonstrated oral absorption to be complete (100%). Absorption via the inhalation route is considered as 100% by default.

Extrapolation from rat oral repeated dose exposure to inhalation exposure:

For workers this factor is reduced to 0.38 m³/kg bw taking into account an 8-hour working shift; in addition a factor of 1.49 correcting for the increased breathing rate for light activity (10m³/8h) compared to base level (6.7m³/8h) is considered.

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov 2012).

AF for differences in duration of exposure:

2

Justification:

In a read across approach to chronic feeding toxicity studies with the disodium salt of sebaic acid, the C10-analog of dodecanedioic acid, in rats and rabbits the highest dose tested showed no adverse effects. NOAEL was 1000 mg/kg bw/d (4.06 mmol corresponding to 935 mg dodecanedioic acid/kg bw/d) for both rats and rabbits. This value corresponds well with the endpoint of 1800 mg/kg bw/d with the default exposure duration assessment factor of 2 included for extrapolation from subchronic to chronic exposure
A default factor of 2 is chosen.

AF for interspecies differences (allometric scaling):

1

Justification:

According to ECHA TGD an allometric scaling factor is not applicable when setting an inhalation DNEL (see Appendix R.8-2 of TGD (ECHA, Nov. 2012)), therefore AF 1 is chosen.

AF for other interspecies differences:

2.5

Justification:

A safety factor of 2.5 for remaining differences is used by default for all exposure routes.

AF for intraspecies differences:

5

Justification:

For intraspecies variability, the default assessment factor for workers is 5.

AF for the quality of the whole database:

1

Justification:

Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for remaining uncertainties:

1

Justification:

No further assessment factors are considered necessary.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

127 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

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:

18 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):

100

Dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Starting point

No adverse effects were noted in a 90-day oral gavage study with rats at the highest dose level tested, the NOAEL was exceeding 1800 mg/kg bw/d. This value is taken as starting point to derive a DNEL_{long term.}

Also no adverse effects were noted in a combined reprotoxicity screening and repeated dose study at the highest dose level of 1000 mg/kg bw/day in rats. Dodecanedioic acid was not genotoxic and there was not carcinogenic activity.

 

Route to route extrapolation

Toxicokinetic studies with experimental animals (rats) and human volunteers demonstrated oral absorption to be complete (100%). As a worst case consideration dermal absorption is considered as 100%.

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for differences in duration of exposure:

2

Justification:

In a read across approach to chronic feeding toxicity studies with the disodium salt of sebaic acid, the C10-analog of dodecanedioic acid, in rats and rabbits the highest dose tested showed no adverse effects. NOAEL was 1000 mg/kg bw/d (4.06 mmol corresponding to 935 mg dodecanedioic acid/kg bw/d) for both rats and rabbits. This value corresponds well with the endpoint of 1800 mg/kg bw/d with the default exposure duration assessment factor of 2 included for extrapolation from subchronic to chronic exposure
A default factor of 2 is chosen.

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA TGD (see section 8.4.3.1 of TGD; ECHA, Nov. 2012) for interspecies extrapolation the default factor of 4 for metabolic differences between rat and humans is considered for both the oral and the dermal exposure route.

AF for other interspecies differences:

2.5

Justification:

A further assessment factor of 2.5 is used by default for dermal/oral exposure according to ECHA TGD (ECHA, Nov. 2012).

AF for intraspecies differences:

5

Justification:

For intraspecies variability, the default assessment factor for workers is 5.

AF for the quality of the whole database:

1

Justification:

Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for remaining uncertainties:

1

Justification:

No further assessment factors are considered necessary.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

Please note: All factors derived below are used in mathematically terms as divisors to derive DNEL(s) from an NOAEL.

With the exception of a reversible irritation in the rabbit eye no adverse local effects were induced by dodecandioic acid. Therefore, no DNEL has to be derived for local effects. A qualitative assessment was performed for eye irritation.

 

Derivation of DNEL_{acute, systemic}

No adverse effects were noted upon acute exposure both in humans upon oral application or in experimental animals upon oral or dermal application. Also no acute adverse effects were noted in repeated dose studies. This means that the DNEL_{long term}is also protective regarding systemic effects for acute exposures.

 

Derivation of DNEL_{long term}

Starting point

No adverse effects were noted in a 90-day oral gavage study with rats at the highest dose level tested, the NOAEL was exceeding 1800 mg/kg bw/d. This value is taken as starting point to derive a DNEL_{long term.}

Also no adverse effects were noted in a combined reprotoxicity screening and repeated dose study at the highest dose level of 1000 mg/kg bw/day in rats. Dodecanedioic acid was not genotoxic and there was not carcinogenic activity.

 

Route to route extrapolation

Toxicokinetic studies with experimental animals (rats) and human volunteers demonstrated oral absorption to be complete (100%). As a worst case consideration dermal absorption is considered as 100%. Absorption via the inhalation route is considered as 100% by default.

Extrapolation from rat oral repeated dose exposure to inhalation exposure:

A factor of 1.15 m³/kg bw is applied, as factor assuming 24h exposure for the general public.

For workers this factor is reduced to 0.38 m³/kg bw taking into account an 8-hour working shift; in addition a factor of 1.49 correcting for the increased breathing rate for light activity (10m³/8h) compared to base level (6.7m³/8h) is considered.

 

Exposure duration extrapolation

In a read across approach to chronic feeding toxicity studies with the disodium salt of sebaic acid, the C10-analog of dodecanedioic acid, in rats and rabbits the highest dose tested showed no adverse effects. NOAEL was 1000 mg/kg bw/d (4.06 mmol corresponding to 935 mg dodecanedioic acid/kg bw/d) for both rats and rabbits. This value corresponds well with the endpoint of 1800 mg/kg bw/d with the default exposure duration assessment factor of 2 included for extrapolation from subchronic to chronic exposure

A default factor of 2 is chosen.

 

Interspecies extrapolation

For interspecies extrapolation the default factor of 4 for metabolic differences between rat and humans is considered for both the oral and the dermal exposure route. This factor is by default not considered relevant for inhalation exposure. In addition a further safety factor of 2.5 for remaining differences is used by default for all exposure routes.

 

Intra-species assessment factors

Default safety factors accounting for intra-species differences in susceptibility (factor 5 for workers and factor 10 for the general population) are assumed.

 

Additional safety factors

No further assessment factors are thought necessary; although there are no data on chronic exposure or multi-generation effects, the overall database indicates that dodecanedioic acid is devoid of any adverse effects because as a regular intermediate in the catabolism of long-chain fatty acids it is incorporated in the mammalian body, utilised as a nutrient in energy production. Assessment factors for dose-response and for quality of the whole database is set on 1.

 

 

 

DNEL_long-term

The DNEL_long-termcalculated, thus, for workers are 18 mg/kg bw/d (dermal route) and 127 mg/m³ for inhalation route. For the general population the DNEL_long-termwere calculated as 9 mg/kg bw/d (oral and dermal route) and 31.3 mg/m³ for inhalation route.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

31.3 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):

57.5

Dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Explanation for the modification of the dose descriptor starting point:

Starting point

No adverse effects were noted in a 90-day oral gavage study with rats at the highest dose level tested, the NOAEL was exceeding 1800 mg/kg bw/d. This value is taken as starting point to derive a DNEL_{long term.}

Also no adverse effects were noted in a combined reprotoxicity screening and repeated dose study at the highest dose level of 1000 mg/kg bw/day in rats. Dodecanedioic acid was not genotoxic and there was not carcinogenic activity.

Route to route extrapolation

Toxicokinetic studies with experimental animals (rats) and human volunteers demonstrated oral absorption to be complete (100%). Absorption via the inhalation route is considered as 100% by default.

Extrapolation from rat oral repeated dose exposure to inhalation exposure: A factor of 1.15 m3/kg bw is applied, as factor assuming 24h exposure of the general public.

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov 2012).

AF for differences in duration of exposure:

2

Justification:

In a read across approach to chronic feeding toxicity studies with the disodium salt of sebaic acid, the C10-analog of dodecanedioic acid, in rats and rabbits the highest dose tested showed no adverse effects. NOAEL was 1000 mg/kg bw/d (4.06 mmol corresponding to 935 mg dodecanedioic acid/kg bw/d) for both rats and rabbits. This value corresponds well with the endpoint of 1800 mg/kg bw/d with the default exposure duration assessment factor of 2 included for extrapolation from subchronic to chronic exposure
A default factor of 2 is chosen.

AF for interspecies differences (allometric scaling):

1

Justification:

According to ECHA TGD an allometric scaling factor is not applicable when setting an inhalation DNEL (see Appendix R.8-2 of TGD (ECHA, Nov. 2012)), therefore AF 1 is chosen.

AF for other interspecies differences:

2.5

Justification:

A safety factor of 2.5 for remaining differences is used by default for all exposure routes.

AF for intraspecies differences:

10

Justification:

For intraspecies variability, the default assessment factor for the general population is 10.

AF for the quality of the whole database:

1

Justification:

Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for remaining uncertainties:

1

Justification:

No further assessment factors are considered necessary.

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:

9 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):

200

Dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Starting point

No adverse effects were noted in a 90-day oral gavage study with rats at the highest dose level tested, the NOAEL was exceeding 1800 mg/kg bw/d. This value is taken as starting point to derive a DNEL_{long term.}

Also no adverse effects were noted in a combined reprotoxicity screening and repeated dose study at the highest dose level of 1000 mg/kg bw/day in rats. Dodecanedioic acid was not genotoxic and there was not carcinogenic activity.

 

Route to route extrapolation

Toxicokinetic studies with experimental animals (rats) and human volunteers demonstrated oral absorption to be complete (100%). As a worst case consideration dermal absorption is considered as 100%.

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for differences in duration of exposure:

2

Justification:

In a read across approach to chronic feeding toxicity studies with the disodium salt of sebaic acid, the C10-analog of dodecanedioic acid, in rats and rabbits the highest dose tested showed no adverse effects. NOAEL was 1000 mg/kg bw/d (4.06 mmol corresponding to 935 mg dodecanedioic acid/kg bw/d) for both rats and rabbits. This value corresponds well with the endpoint of 1800 mg/kg bw/d with the default exposure duration assessment factor of 2 included for extrapolation from subchronic to chronic exposure
A default factor of 2 is chosen.

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA TGD (see section 8.4.3.1 of TGD; ECHA, Nov. 2012) for interspecies extrapolation the default factor of 4 for metabolic differences between rat and humans is considered for both the oral and the dermal exposure route.

AF for other interspecies differences:

2.5

Justification:

A further assessment factor of 2.5 is used by default for dermal/oral exposure according to ECHA TGD (ECHA, Nov. 2012).

AF for intraspecies differences:

10

Justification:

For intraspecies variability, the default assessment factor for the general population is 10.

AF for the quality of the whole database:

1

Justification:

Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for remaining uncertainties:

1

Justification:

No further assessment factors are considered necessary.

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:

9 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):

200

Dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 800 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Starting point

No adverse effects were noted in a 90-day oral gavage study with rats at the highest dose level tested, the NOAEL was exceeding 1800 mg/kg bw/d. This value is taken as starting point to derive a DNEL_{long term.}

Also no adverse effects were noted in a combined reprotoxicity screening and repeated dose study at the highest dose level of 1000 mg/kg bw/day in rats. Dodecanedioic acid was not genotoxic and there was not carcinogenic activity.

AF for dose response relationship:

1

Justification:

Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for differences in duration of exposure:

2

Justification:

n a read across approach to chronic feeding toxicity studies with the disodium salt of sebaic acid, the C10-analog of dodecanedioic acid, in rats and rabbits the highest dose tested showed no adverse effects. NOAEL was 1000 mg/kg bw/d (4.06 mmol corresponding to 935 mg dodecanedioic acid/kg bw/d) for both rats and rabbits. This value corresponds well with the endpoint of 1800 mg/kg bw/d with the default exposure duration assessment factor of 2 included for extrapolation from subchronic to chronic exposure
A default factor of 2 is chosen.

AF for interspecies differences (allometric scaling):

4

Justification:

According to ECHA TGD (see section 8.4.3.1 of TGD; ECHA, Nov. 2012) for interspecies extrapolation the default factor of 4 for metabolic differences between rat and humans is considered for both the oral and the dermal exposure route.

AF for other interspecies differences:

2.5

Justification:

A further assessment factor of 2.5 is used by default for dermal/oral exposure according to ECHA TGD (ECHA, Nov. 2012).

AF for intraspecies differences:

10

Justification:

For intraspecies variability, the default assessment factor for the general population is 10.

AF for the quality of the whole database:

1

Justification:

Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).

AF for remaining uncertainties:

1

Justification:

No further assessment factors are considered necessary.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL extrapolated from long term DNEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Please note: All factors derived below are used in mathematically terms as divisors to derive DNEL(s) from an NOAEL.

With the exception of a reversible irritation in the rabbit eye no adverse local effects were induced by dodecandioic acid. Therefore, no DNEL has to be derived for local effects.A qualitative assessment was performed for eye irritation.

 

Derivation of DNEL_{acute, systemic}

No adverse effects were noted upon acute exposure both in humans upon oral application or in experimental animals upon oral or dermal application. Also no acute adverse effects were noted in repeated dose studies. This means that the DNEL_{long term}is also protective regarding systemic effects for acute exposures.

 

Derivation of DNEL_{long term}

Starting point

No adverse effects were noted in a 90-day oral gavage study with rats at the highest dose level tested, the NOAEL was exceeding 1800 mg/kg bw/d. This value is taken as starting point to derive a DNEL_{long term.}

Also no adverse effects were noted in a combined reprotoxicity screening and repeated dose study at the highest dose level of 1000 mg/kg bw/day in rats. Dodecanedioic acid was not genotoxic and there was not carcinogenic activity.

 

Route to route extrapolation

Toxicokinetic studies with experimental animals (rats) and human volunteers demonstrated oral absorption to be complete (100%). As a worst case consideration dermal absorption is considered as 100%. Absorption via the inhalation route is considered as 100% by default.

Extrapolation from rat oral repeated dose exposure to inhalation exposure:

A factor of 1.15 m³/kg bw is applied, as factor assuming 24h exposure for the general public.

For workers this factor is reduced to 0.38 m³/kg bw taking into account an 8-hour working shift; in addition a factor of 1.49 correcting for the increased breathing rate for light activity (10m³/8h) compared to base level (6.7m³/8h) is considered.

 

Exposure duration extrapolation

In a read across approach to chronic feeding toxicity studies with the disodium salt of sebaic acid, the C10-analog of dodecanedioic acid, in rats and rabbits the highest dose tested showed no adverse effects. NOAEL was 1000 mg/kg bw/d (4.06 mmol corresponding to 935 mg dodecanedioic acid/kg bw/d) for both rats and rabbits. This value corresponds well with the endpoint of 1800 mg/kg bw/d with the default exposure duration assessment factor of 2 included for extrapolation from subchronic to chronic exposure

A default factor of 2 is chosen.

 

Interspecies extrapolation

For interspecies extrapolation the default factor of 4 for metabolic differences between rat and humans is considered for both the oral and the dermal exposure route. This factor is by default not considered relevant for inhalation exposure. In addition a further safety factor of 2.5 for remaining differences is used by default for all exposure routes.

 

Intra-species assessment factors

Default safety factors accounting for intra-species differences in susceptibility (factor 5 for workers and factor 10 for the general population) are assumed.

 

Additional safety factors

No further assessment factors are thought necessary; although there are no data on chronic exposure or multi-generation effects, the overall database indicates that dodecanedioic acid is devoid of any adverse effects because as a regular intermediate in the catabolism of long-chain fatty acids it is incorporated in the mammalian body, utilised as a nutrient in energy production. Assessment factors for dose-response and for quality of the whole database is set on 1.

DNEL_long-term

The DNEL_long-termcalculated, thus, for general population are 9 mg/kg bw/d (dermal and oral route) and 31.3 mg/m³ for inhalation route.

Setting of DNEL is considered high conservative because dodecanedioic acid did not induce any toxic effects in the available studies.