N,N',N'',N'''-tetrakis(4,6-bis(butyl-(N-methyl-2,2,6,6-tetramethylpiperidin-4-yl)amino)triazin-2-yl)-4,7-diazadecane-1,10-diamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.176 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:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

4.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Due to lack of repeated dose toxicity data by the inhalation route, a route to route extrapolation was performed. The NOAEL (oral) is converted into a NOAEC (corrected) in accordance to guidance on information requirements and chemical safety assessment, Chapter R.8, ECHA, May 2008. The NOAEL (oral) has to be divided by a factor of 0.38 m³/kg body weight and multiplicated by using the default value of 2 to consider the ratio of oral (rat) to inhalation (human) absorption. Then, the NOAEL has to be corrected for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m³/10 m³). The corrected starting point is therefore:

NOAEC (corrected) = 5 mg/kg / 0.38 m³/kg x 2 x (6.7 m³/10m³) = 4.4 mg/m³

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:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is part of the route to route extrapolation

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

GLP and guideline compliant study

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 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:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin permeation is available. However, since the test article has a molecular weight of > 500 and the log POW is not within -1 to 4, a skin penetration of 10% can be assumed and an assessment factor of 0.1 is applied (ECHA GD chapter R7c). Modified NOAEL = 5 mg/kg * 10 = 50 mg/kg body weight.

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:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

extrapolation from rat to human

AF for other interspecies differences:

2.5

Justification:

standard factor for remaining uncertainties

AF for intraspecies differences:

5

Justification:

standard factor for worker

AF for the quality of the whole database:

1

Justification:

GLP studies compliant with international guideline

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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Identification of relevant dose descriptor

For the derivation of the DNELs, the 90-day oral repeated dose toxicity study in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 5 mg/kg/day.

 

General information on toxicity:

The substance is almost entirely eliminated with the feces shortly after oral application. This is consistent with the very high molecular weight that prevents passive uptake via biological membranes. Accordingly, it shows no acute toxicity. It is neither irritant to skin nor eyes. It is not genotoxic in vitro. Its adverse effects appear to be mediated by uptake via specialized macrophages in the small intestine, because the cell proliferation in the mesenteric lymph nodes are the first effects observed in long-term feeding studies. At higher doses, activated macrophages also occur in other organs (large intestine, liver, kidney, adrenal cortex, spleen and ovaries). In some cases, this leads to secondary inflammatory lesions and/or partial necrosis in parallel to slight to moderate dysfunctional changes. In blood, an overall activation of the white blood cell system activity is observed. It is possible that the radical-scavenging properties of the substance slow the degradation within the macrophages. Findings at the high dose group of 100 mg/kg bw were not reversible within the 28 -day recovery period. The substance is a strong dermal sensitizer.

General Population - Hazard via inhalation 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:

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:

0.25 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:

5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The dermal route is typically covered by oral route information in the absence of data for this administration route. No data on skin permeation is available. However, since the test article has a molecular weight of > 500 and the log POWis not within -1 to 4, a skin penetration of 10% can be assumed and an assessment factor of 0.1 is applied (ECHA GD chapter R7c).

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):

4

Justification:

The default allometric scaling factor for the differences between rats 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:

GLP studies compliant with international guideline

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:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.025 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:

5 mg/kg bw/day

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):

4

Justification:

The default allometric scaling factor for the differences between rats 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:

GLP studies compliant with international guideline

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

For the derivation of the DNELs, the 90-day oral repeated dose toxicity study in rats was qualified as the most relevant study. The dose descriptor chosen was the NOAEL of 5 mg/kg/day.