Reaction mass of 2-(1,1-dimethylpropyl)anthraquinone and 2-(1,2-dimethylpropyl)anthraquinone

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.88 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):

25

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

22 mg/m³

Explanation for the modification of the dose descriptor starting point:

Based on 50% oral and 100% inhalation absorption and considering a standard respiratory volume of 0.38 m³/kg/day in rat, a standard respiratory volume of 6.7 m³/8 hours for a person at rest and 10 m³/volume for a worker performing light activity.

AF for dose response relationship:

1

Justification:

There is no indication of a steep dose-response, and a reliable NOAEL can be derived based on the dose range tested.

AF for differences in duration of exposure:

2

Justification:

Assuming chronic exposure and extrapolating from a subchronic study.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling included in dose descriptor starting point, see below described conversion

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default

AF for the quality of the whole database:

1

Justification:

Data from a reliable guideline study

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 250 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Assuming 50% oral and 1% dermal absorption for the pure substance. Furthermore, an additional DNEL for the exposure to the substance in formulation has been derived, see discussion below.

AF for dose response relationship:

1

Justification:

There is no indication of a steep dose-response, and a reliable NOAEL can be derived based on the dose range tested.

AF for differences in duration of exposure:

2

Justification:

Assuming chronic exposure of the worker and extrapolating from a subchronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Default for rat to human

AF for other interspecies differences:

2.5

Justification:

Default

AF for intraspecies differences:

5

Justification:

Default

AF for the quality of the whole database:

1

Justification:

Based on a reliable guideline study.

AF for remaining uncertainties:

1

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

Derivation of DNELs

The DNELs for human exposure are derived according to the ECHA guidance.

 

Local DNELs: 2-amylanthraquinone is non-irritating to the eyes and skin, and need not to be classified for irritating properties. Therefore, no acute local DNELs need to be derived.

Acute DNEL’s: Acute DNELs are only required/considered relevant if the substance is classified for acute toxicity. Generally only for the inhalation route acute DNEL’s are considered relevant, in order to account for peak exposures. Although peak exposure in theory also may occur for the dermal and oral route, these are not normally assessed, so the establishment of acute toxicity DNELs for dermal and oral peak exposures appears superfluous. The long-term DNEL is normally sufficient to ensure that acute effects do not appear.

2-Amylanthraquinone is classified for acute oral toxicity, but not classified for acute inhalation and dermal effects (no acute studies with those routes of exposure available), and therefore no acute DNELs are derived.

Starting point for DNEL derivation is the no adverse effect level in a relevant study. DNELs are derived based on the available 90 -day oral toxicity study in rats. As starting point of the DNELs for 2-amylanthraquinone, the NOAEL of 25 mg/kg bw/day as concluded in this study has been used.

Systemic effects – long term

Starting point: NOAEL of 25 mg/kg bw/day in an oral 90-day repeated dose toxicity study in rats.

Oral absorption: 50%

Dermal absorption: 50% for a substance in formulation and 1% for pure substance.

Inhalation absorption: 100%

Dermal – worker

As different dermal absorption values were obtained for the pure substance and the substance in a formulation, two dermal DNELs for workers have been derived. As the IUCLID format does not allow to enter two DNELs for the same exposure route and duration, the DNEL derived for the pure substance is included above. However, for completeness purposes both DNELs are reported below.

Correction dermal NOAEL for the pure substance: 25 x 50/1^a= 1250 mg/kg bw/day

Correction dermal NOEAL for the substance in a formulation: 25 x 50/50^a = 25 mg/kg bw/day

Correction

^a: oral/dermal absorption

 

Safety factors (ECHA):

-          Interspecies extrapolation: 4 x 2.5 (allometric scaling and other interspecies differences)

-          Intraspecies extrapolation: 5

-          Exposure duration: 2 (assuming chronic exposure of the worker and extrapolating from a subchronic study)

-          Dose response: 1

-          Quality of the data base: 1

Total safety factor: 100

 

Based on the above, the long-term DNEL for systemic effects after dermal exposure of the worker is set at 12.5 mg/kg bw/day for the pure substance and 0.25 mg/kg bw/day for the substance in a formulation.

Inhalation – worker

Conversion of an oral rat NOAEL into a corrected NOAEC:

 

For workers (8h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABS_oral-rat/ABS_inhal-human* sRV_human/wRV

 

           = oral NOAEL * 1/0.38 m³/kg/8h * ABS_oral-rat/ABS_inhal-human* 6.7 m³(8h)/10 m³(8h)

 

           = oral NOAEL * 1/0.38 m³/kg/8h * 50/100 * 6.7 m³(8h)/10 m³(8h)

 

= 25 /0.38 * 0.5 * (6.7/10) = 22.0 mg/m³.

 

With ABS: Absorption, sRV: Standard Respiratory Volume; wRV: Worker Respiratory Volume;

ABS_oral-rat/ABS_inhal-human= 0.5, assuming no differences in inhalation absorption between rats and humans.

 

Safety factors (ECHA):

-          Interspecies extrapolation: 2.5 (other interspecies differences, no correction for allometric scaling as included in the above conversion)

-          Intraspecies extrapolation: 5

-          Exposure duration: 2 (assuming chronic exposure of the worker and extrapolating from a subchronic study)

-          Dose response: 1

-          Quality of the data base: 1

Total safety factor: 25

 

Based on the above, the long-term DNEL for systemic effects after inhalation exposure of the worker is set at 0.88 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.22 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):

50

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

10.9 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

2.5

AF for other interspecies differences:

1

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.125 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

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:

0.125 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

other: no modification of the starting point is necessary, as the DNEL is derived from an oral repeated dose toxicity study.

Explanation for the modification of the dose descriptor starting point:

Not relevant, as no modification of the starting point is necessary.

AF for dose response relationship:

1

Justification:

There is no indication of a steep dose-response, and a reliable NOAEL can be derived from the dose range tested.

AF for differences in duration of exposure:

2

Justification:

Assuming chronic exposure for general population and extrapolating from a subchronic study.

AF for interspecies differences (allometric scaling):

4

Justification:

Default from rat to human

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default

AF for the quality of the whole database:

1

Justification:

Based on a reliable guideline study.

AF for remaining uncertainties:

1

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:

no hazard identified

Additional information - General Population

Derivation of DNELs

The DNELs for human exposure are derived according to the ECHA guidance.

 

Local DNELs: 2-amylanthraquinone is non-irritating to the eyes and skin, and need not to be classified for irritating properties. Therefore, no acute local DNELs need to be derived.

Acute DNEL’s: Acute DNELs are only required/considered relevant if the substance is classified for acute toxicity. Generally only for the inhalation route acute DNEL’s are considered relevant, in order to account for peak exposures. Although peak exposure in theory also may occur for the dermal and oral route, these are not normally assessed, so the establishment of acute toxicity DNELs for dermal and oral peak exposures appears superfluous. The long-term DNEL is normally sufficient to ensure that acute effects do not appear.

2-Amylanthraquinone is classified for acute oral toxicity, but not classified for acute inhalation and dermal effects (no acute studies with those routes of exposure available), and therefore no acute DNELs are derived.

 

Starting point for DNEL derivation is the no adverse effect level in a relevant study. DNELs are derived based on the available 90-day oral toxicity study in rats. As starting point of the DNELs for 2-amylanthraquinone, the NOAEL of 25 mg/kg as concluded in this study has been used.

 

Systemic effects – long term

Starting point: NOAEL of 25 mg/kg bw/day in an oral 90-day repeated dose toxicity study in rats.

Oral absorption: 50%

Dermal absorption: 50% for a substance in a formulation (it is not expected that general population shall come into contact with the undiluted substance).

Inhalation absorption: 100%

 

Oral – general population

Safety factors (ECHA):

-         Interspecies extrapolation: 4x2.5 (rat to human and other differences)

-         Intraspecies extrapolation: 10

-         Exposure duration: 6 (assuming chronic exposure of the general population and extrapolating from a subchronic study)

-         Dose response: 1

-         Quality of the data base: 1

Total safety factor: 200

 

Based on the above, the long-term DNEL for systemic effects after oral exposure of the general population is set at 0.125 mg/kg bw/day.

 

Dermal – general population

Correction dermal NOAEL: 25 x 50/50^a= 25 mg/kg bw/day

^a: oral/dermal absorption

 

Safety factors (ECHA):

-          Interspecies extrapolation: 4x2.5 (rat to human and other differences)

-          Intraspecies extrapolation: 10

-          Exposure duration: 2 (assuming chronic exposure for general population and extrapolating from a subchronic study)

-          Dose response: 1

-          Quality of the data base: 1

Total safety factor: 200

 

Based on the above, the long-term DNEL for systemic effects after dermal exposure of the general population is set at 0.125 mg/kg bw/day.

 

Inhalation – general population

Conversion of an oral rat NOAEL into a corrected NOAEC:

For the general population (24h exposure/day), the corrected inhalatory NOAEC = oral NOAEL * 1/sRVrat * ABS_oral-rat/ABS_inhal-human

           = oral NOAEL * 1/1.15 m³/kg/d * ABS_oral-rat/ABS_inhal-human =

= (25 /1.15) * 0.5 = 10.9 mg/m³.

 

With ABS: Absorption, sRV: Standard Respiratory Volume.

 

Safety factors (ECHA):

-          Interspecies extrapolation: 2.5 (no correction for caloric demand for inhalation, for other differences)

-          Intraspecies extrapolation: 10

-          Exposure duration: 2 (assuming chronic exposure of the general population and extrapolating from a subchronic study)

-          Dose response: 1

-          Quality of the data base: 1

Total safety factor: 50

Based on the above, the long-term DNEL for systemic effects after inhalation exposure of the general population is set at 0.22 mg/m3.