2,2'-methylenebis(6-nonyl-p-cresol)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.8 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:

139 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEL(oral) converted to NOAEC(inhal) (158 mg/kg x [1/0.38 x 50% oral absorption rat/100% inhalation absorption human x 6.7/10]) = 139 mg/m³

AF for dose response relationship:

1

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for differences in duration of exposure:

2

Justification:

Extrapolation from subchronic study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

Justification:

Differences in species addressed in calculation of dose descriptor starting point

Justification:

Differences in species addressed in calculation of dose descriptor starting point

AF for intraspecies differences:

5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for the quality of the whole database:

2

Justification:

Limited information on chronic, reproductive and developmental toxicity. (OECD 421 study on highly similar read across substance only)

AF for remaining uncertainties:

2.5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

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 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

Modified dose descriptor starting point:

NOAEL

Value:

790 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL (oral) converted to NOAEL (dermal): 158 mg/kg bw/day*50% ABS (oral)/10%ABS(dermal) = 790 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for differences in duration of exposure:

2

Justification:

Extrapolation from subchronic study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for interspecies differences (allometric scaling):

4

Justification:

Default value in line with Table R.8-3 and Appendix R. 8-2, part 2, example B5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

Justification:

Differences in species addressed in calculation of dose descriptor starting point.

AF for intraspecies differences:

5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

AF for the quality of the whole database:

2

Justification:

Limited information on chronic, reproductive and developmental toxicity. (OECD 421 study on highly similar read across substance only)

AF for remaining uncertainties:

2.5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment.

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

2,2'-methylenebis(6-nonyl-p-cresol) is not classified for skin/eye irritation or skin sensitisation and is not expected to show any local effects; DNELs for acute exposure and local effects were therefore not calculated. The substance does not possess any genotoxic potential.

The most sensitive endpoint was the NOAEL (158 mg/kg bw/day) obtained in an acceptable 90-day feeding study in rats. The study was performed in line with good scientific principles and reported to a high standard. In accordance with Klimisch (1997) the study was assigned a reliability score of 1. This NOAEL was used as the starting point for the calculation of systemic DNELs. The reproductive and developmental toxicity was investigated in a study performed in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550 using an appropriate test material suitable for read-across to support 2,2'-methylene-bis(6-nonyl-p-cresol); this study showed no effect at the highest dose tested. Also by read-across, no evidence of carcinogenicity was seen in acceptable studies; however the highest doses tested for carcinogenicity by read-across were of the same magnitude as the key 90-day NOAEL of the test material. An additional factor of 2 for completeness of the database is therefore applied.

For the purposes of human risk assessment there is sufficient information to consider that 2,2'-methylene-bis(6-nonyl-p-cresol) would be partially absorbed (50%) by the oral route, and slowly metabolised and excreted. The consequences of slow metabolism and excretion are however adequately addressed within the NOAEL of a 90-day study. Human dermal absorption may be considered to be 10%; inhalation absorption is assumed to be complete.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 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):

100

Modified dose descriptor starting point:

NOAEC

Value:

69 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEL(oral) converted to NOAEC(inhal) (158 mg/kg x [1/1.15 x 50% oral absorption rat/100% inhalation absorption human) = 69 mg/m³

AF for dose response relationship:

1

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for differences in duration of exposure:

2

Justification:

Extrapolation from subchronic study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

Justification:

Differences in species addressed in calculation of dose descriptor starting point

Justification:

Differences in species addressed in calculation of dose descriptor starting point

AF for intraspecies differences:

10

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for the quality of the whole database:

2

Justification:

Limited information on chronic, reproductive and developmental toxicity. (OECD 421 study on highly similar read across substance only)

AF for remaining uncertainties:

2.5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

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 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

790 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAEL (oral) converted to NOAEL (dermal): 158 mg/kg bw/day*50% ABS (oral)/10%ABS(dermal) = 790 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for differences in duration of exposure:

2

Justification:

Extrapolation from subchronic study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for interspecies differences (allometric scaling):

4

Justification:

Default value in line with Table R.8-3 and Appendix R. 8-2, part 2, example B5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

Justification:

Differences in species addressed in calculation of dose descriptor starting point

AF for intraspecies differences:

10

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for the quality of the whole database:

2

Justification:

Limited information on chronic, reproductive and developmental toxicity. (OECD 421 study on highly similar read across substance only)

AF for remaining uncertainties:

2.5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

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:

0.4 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

158 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Assumed that the oral absorption in rat and humans is the same

AF for dose response relationship:

1

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for differences in duration of exposure:

2

Justification:

Extrapolation from subchronic study to chronic exposure value in line with Table R.8-5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for interspecies differences (allometric scaling):

4

Justification:

Default value in line with Table R.8-3 and Appendix R. 8-2, part 2, example B5 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

Justification:

Differences in species addressed in calculation of dose descriptor starting point

AF for intraspecies differences:

10

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

AF for the quality of the whole database:

2

Justification:

Limited information on chronic, reproductive and developmental toxicity. (OECD 421 study on highly similar read across substance only)

AF for remaining uncertainties:

2.5

Justification:

Default value in line with Section R.8.4.3.1 of Chapter R.8 of Guidance on information requirements and chemical safety assessment

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

2,2'-methylenebis(6-nonyl-p-cresol) is not classified for skin/eye irritation or skin sensitisation and is not expected to show any local effects; DNELs for acute exposure and local effects were therefore not calculated. The substance does not possess any genotoxic potential.

The most sensitive endpoint was the NOAEL (158 mg/kg bw/day) obtained in an acceptable 90-day feeding study in rats. The study was performed in line with good scientific principles and reported to a high standard. In accordance with Klimisch (1997) the study was assigned a reliability score of 1. This NOAEL was used as the starting point for the calculation of systemic DNELs. The reproductive and developmental toxicity was investigated in a study performed in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550 using an appropriate test material suitable for read-across to support 2,2'-methylene-bis(6-nonyl-p-cresol); this study showed no effect at the highest dose tested. Also by read-across, no evidence of carcinogenicity was seen in acceptable studies; however the highest doses tested for carcinogenicity by read-across were of the same magnitude as the key 90-day NOAEL of the test material. An additional factor of 2 for completeness of the database is therefore applied.

For the purposes of human risk assessment there is sufficient information to consider that 2,2'-methylene-bis(6-nonyl-p-cresol) would be partially absorbed (50%) by the oral route, and slowly metabolised and excreted. The consequences of slow metabolism and excretion are however adequately addressed within the NOAEL of a 90-day study. Human dermal absorption may be considered to be 10%; inhalation absorption is assumed to be complete.

The same endpoint used for workers was selected for setting the long-term DNELs for the general population. The larger assessment factor for intraspecies sensitivity was considered adequately protective for the more sensitive population.