Registration Dossier

Administrative data

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
DNEL 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
DNEL 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
DNEL 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
DNEL 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
DNEL 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.