Hexamethylene bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate]

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

DNEL related information

DNEL derivation method:

other: The general exposure limit for inhalable dust is applied

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

DNEL related information

DNEL derivation method:

other: The general exposure limit for inhalable dust is applied

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:

42.5 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):

35

Modified dose descriptor starting point:

NOAEL

Value:

1 487 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absorption is anticipated to be 10 % of oral absorption.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dogs and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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

Identification of relevant dose descriptor

In the rats, the test article caused responses in liver and thyroid that are known to be species specific for this substance class, and therefore, these findings are of no relevance for man. For risk assessment and the derivation of the DNELs, the 90 day oral toxicity study in dogs was therefore qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 148.7 mg/kg/day.

Calculation of DNELs

Systemic, long-term, dermal:

DNEL = NOAEL (oral) / Sum of assessment factors applicable

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin penetration is available for the test article. However, since the test article has a molecular weight of > 500 and the log P_OW is not within -1 to 4, a skin penetration of 10% can be assumed and the starting point is modified accordingly, resulting in a NOAEL of 1487 mg/kg bw (ECHA GD chapter R7c). The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 5

Interspecies variations: 2.5

Allometric scaling (rat to human): 1.4

Exposure duration: 2

Dose-response factor: 1

Quality of whole database factor: 1

Overall, an assessment factor of 35 was employed for the dermal route.

DNEL= 1487 mg/kg body weight / 35 = 42.5 mg/kg body weight.

Systemic, long-term, inhalative

According to ECHA guidelines, a route to route extrapolation is performed if no information by the inhalative route is available. Following ECHA guidance document Chapter R.8 the NOAEL (oral) has to be adjusted for differences in respiratory volume for test animals and humans and corrected for activity driven differences of respiratory volumes in workers compared to workers in rest, resulting in a corrected starting point of 749.1 mg/m³. The DNEL is calculated as follows: NOAEL (corrected) / Sum of assessment factors applicable.

The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (worker): 5

Interspecies variations: 2.5

Exposure duration: 2

Default factor to account for differences in oral and inhalative absorption properties: 2

Dose-response factor: 1

Quality of whole database factor: 1

The overall assessment factor employed for the inhalation route is therefore 50.

DNEL = 749.1 mg/m³/ 50 = 14.98 mg/m³

 

However, since the substance is a solid with low solubility for which no relevant systemic hazard was identified by the oral route, the systemic DNEL derived above is considered not relevant. The main hazard results if dusty material is inhaled at doses at which the natural clearance function of the lung is overloaded. To protect against this effect, the general exposure limit of 10 mg/m³ for inhalable dust is applied.

 

Systemic, short-term, dermal and inhalative

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated. Regarding exposure by inhalation, the main hazard results if dusty material is inhaled at doses at which the natural clearance function of the lung is overloaded. To protect against this hazard, the general exposure limit for inhalable dust is applied. This value is considered to give also sufficient protection for acute effects.

 

Local, long-term and short-term, inhalative

The main hazard results if dusty material is inhaled at doses at which the natural clearance function of the lung is overloaded. To protect against this effect, the general exposure of limit of 10 mg/m³ for inhalable inert dust is applied.

 

Local, long-term and short-term, dermal

Based on the available key toxicological information, the test item is not subject to classification for skin and eye irritation and skin sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.69 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

Modified dose descriptor starting point:

NOAEC

Value:

184.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

21.2 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):

70

Modified dose descriptor starting point:

NOAEL

Value:

1 487 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be 10 % of oral absorption.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dogs and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

2.1 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):

70

Modified dose descriptor starting point:

NOAEL

Value:

148.7 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required since a repeated dose oral toxicity study is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dogs and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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

Identification of relevant dose descriptor

The dose descriptor chosen is the same as for workers (see above). The NOAEL of 148.7 mg/kg observed in the 90-day repeated dose study in dogs was used as starting point to derive the DNELs.

 

Calculation of DNELs

Systemic, long-term, dermal:

DNEL = NOAEL (oral) / Sum of assessment factors applicable

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin penetration is available for the test article. However, since the test article has a molecular weight of > 500 and the log P_OW is not within -1 to 4, a skin penetration of 10% can be assumed and the starting point is modified accordingly, resulting in a NOAEL of 1487 mg/kg bw (ECHA GD chapter R7c). The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (general population): 10

Interspecies variations: 2.5

Allometric scaling (dog to human): 1.4

Exposure duration: 2

Oral to dermal route extrapolation factor: 0.1

Dose-response factor: 1

Quality of whole database factor: 1

Overall, an assessment factor of 70 was employed for the dermal route.

DNEL= 1487 mg/kg body weight / 70 = 21.2 mg/kg body weight.

Systemic, long-term, inhalative

Because no inhalation study is available, a route to route extrapolation was performed. The NOAEL (oral) has to be adjusted into a NOAEL (corrected) based on differences in respiratory volumes for test animals (dogs) and humans in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. In addition, a default factor of 2 is applied to account for differences in oral and inhalative absorption properties. The corrected starting point here is 184.4 mg/m³ per day. The DNEL is calculated as follows:

NOAEL (corrected) / Sum of assessment factors applicable.

The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (general population): 10

Interspecies variations: 2.5

Exposure duration: 2

Dose-response factor: 1

The overall assessment factor employed for the inhalation route is therefore 50.

DNEL = 184.4 mg/m³/ 100 = 3.69 mg/m³

Systemic, long-term, oral:

The NOAEL of 148.7 mg/kg body weight observed in the subchronic study in dogs was used as starting point for DNEL derivation. The following assessment factors according to "ECHA guidance on information requirements and chemical safety assessment, Chapter R8" were chosen:

Intraspecies differences (general population): 10

Interspecies variations: 2.5

Allometric scaling (dog to human): 1.4

Exposure duration: 2

Dose-response factor: 1

Quality of whole database factor: 1

Overall, an assessment factor of 70 was employed for the dermal route.

DNEL= 148.7 mg/kg body weight / 70 = 2.1 mg/kg body weight.

 

Systemic, short-term, oral, dermal and by inhalation

According to the ECHA document "Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose[concentration]-response for human health", a DNEL for acute systemic toxicity should only be derived if an acute systemic toxicity hazard leading to classification is identified. Therefore, because the substance is not classified for acute toxicity according to Directive 67/548/EEC and Regulation 1272/2008/EC, no systemic DNELs for short-term exposures were calculated.

 

Local, long-term and short-term, dermal

Based on the available key toxicological information, the test item is not subject to classification for skin and eye irritation and skin sensitization (according to 67/548/EEC and EC/1272/2008). Accordingly, no DNELs for local effects following acute/short-term or long-term exposure are derived. This is in line with the ECHA guidance document (Chapter R.8).