Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

225

Modified dose descriptor starting point:

NOAEC

Value:

881.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

A long-term systemic inhalation DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that the oral absorption rate is 50% that of the inhalation rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for workers is derived as: oral NOAEL x (1/0.38 m3/kg/day) x (6.7 m3/10m3 (8 h)) x (% oral absorption/ % inhalation absorption) = 1000 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 881.6 mg/m3.

AF for dose response relationship:

1

Justification:

A default factor: based on the available data, the substance is of low toxicity

AF for differences in duration of exposure:

6

Justification:

A default factor for extrapolation from a sub-acute study to chronic exposure.

AF for other interspecies differences:

2.5

Justification:

Default factor (remaining differences)

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

3

Justification:

No analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

900

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A long-term systemic dermal DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 1000 mg/kg bw/day x (50/50) = 1000 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

A default factor: based on the available data, the substance is of low toxicity

AF for differences in duration of exposure:

6

Justification:

A default factorfor extrapolation from a sub-acute study to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor: (allometric scaling: rat)

AF for other interspecies differences:

2.5

Justification:

Default factor (remaining differences)

AF for intraspecies differences:

5

Justification:

Default factor for workers

AF for the quality of the whole database:

1

Justification:

A default factor

AF for remaining uncertainties:

3

Justification:

No analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Identity of the substance and approach to meeting the data requirements

Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines

Toxicokinetics

Based on physicochemical data, toxicity data and theoretical assessment, the basic toxicokinetics of Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines can be adequately characterised. According to Lipinski’s Rule of Five (OECD QSAR Toolbox prediction using a representative structure), the substance will not be bioavailable, therefore oral absorption is not predicted. Dermal absorption is also considered to be unlikely. No reliable quantitative prediction of the extent of inhalation absorption can be made; however inhalation absorption is also likely to be low.

Acute toxicity

The acute oral toxicity of Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines is low. The oral LD₅₀of the substance was determined to be > 2000 mg/kg bw in rats in an acute oral toxicity study (OECD Test Guideline 423) whereas the dermal LD₅₀of the substance was determined to be > 2000 mg/kg bw in rats in an acute dermal toxicity study (OECD Test Guideline 402). A waiver is proposed in accordance with Column 2 of Annex VIII of the REACH Regulation for acute inhalation toxicity on the basis that acute toxicity data are available for the oral and dermal routes. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties of the substance.

Irritation/corrosion

Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines was not corrosive in an in vitro study using the EpiDerm™ skin model. Based on available evidence from other polyamidamine substances, the substance is considered to have the potential to cause skin irritation. Based on read-across to an in vivo eye irritation study using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine, the substance is considered to be highly irritating to the eyes.

Skin sensitisation

Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines was considered to be a skin sensitiser in the Local Lymph Node Assay (LLNA) conducted according to OECD Test Guideline 429. The substance meets the criteria for classification for skin sensitisation as: Category 1A, H317 "May cause an allergic skin reaction" according to Regulation (EC) No 1272/2008 and as Xi, R43 "May cause sensitisation by skin contact" according to Directive 67/548/EEC.

Repeated dose toxicity

Based on existing datasets and structural ad chemical considerations, read-across from Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines to an available repeated dose toxicity study using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is appropriate to meet the REACH Annex VII-IX data requirements. In a combined repeated dose and reproduction/developmental toxicity screening test conducted in the rat according to OECD Test Guideline 422, the NOAEL for systemic toxicity was determined to be 1000 mg/kg bw/day (i.e. the highest dose tested). The repeated dose toxicity of the substance will be characterised further based on read-across to a proposed 90-day oral repeated dose toxicity study in the rat (OECD Test Guideline 408) using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine.

Genetic toxicity

No evidence of mutagenicity was seen for Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines in a bacterial reverse mutation assay (Ames test). Based on existing datasets and structural and chemical considerations, read-across from the substance to genotoxicity studies on Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is appropriate to meet the REACH Annex VII-IX data requirements. Negative results were obtained in in vitro mammalian cytogenicity and gene mutation studies with Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine. Based on read-across to these studies, the substance is not predicted to be genotoxic in vitro in mammalian cell systems.

Toxicity to reproduction

Based on existing datasets and structural ad chemical considerations, read-across from Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines to an available study using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is appropriate to meet the REACH Annex VII-IX data requirements. In a combined repeated dose and reproduction/developmental toxicity screening test conducted in the rat according to OECD Test Guideline 422, no effects on reproductive parameters were observed at doses up to 1000 mg/kg bw/day (i.e. the highest dose tested). The reproductive toxicity of the substance will be characterised further based on read-across to a proposed 90-day oral repeated dose toxicity study (OECD Test Guideline 408) and a prenatal developmental toxicity study (OECD 414) conducted using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine.

Read-across to the findings of a proposed pre-natal developmental toxicity study (OECD Test Guideline 414) on Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is considered appropriate for the characterisation of the developmental toxicity hazard potential of Fatty acids, C18-unsatd., dimers, reaction products with polyethylenepolyamines.

DNEL derivation [Workers]

Based on the data available, the substance is of low acute toxicity, is not mutagenic, does not cause target organ or systemic toxicity and is not a developmental or reproductive toxin. The substance is irritating to the skin and the eyes and is a skin sensitiser. Classification in respect of these effects is proposed.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 1000 mg/kg bw/day from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422 using the read-across substance: Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine.

Local effects

DNEL values for local inhalation effects are not derived. No data are available regarding local respiratory effects. Since the substance is irritating to the skin and the eyes, local inhalation effects following acute or repeated exposures would be manifested by respiratory irritation. Due to the very low vapour pressure of the substance, inhalation exposures would only be possible in the form of aerosol, consisting of larger droplets depositing in the upper airways which could result in local irritation. However, as no dose-response data regarding local respiratory effects are available, a quantitative dose descriptor (e.g. a DNEL) cannot be calculated based on available information. The absence of route specific information is justified based on conditions of use and qualitative risk characterisation.

DNEL values for local dermal effects are not derived. The substance is irritating and sensitising to the skin. The substance is classified for skin irritation as: Category 2, H315 “Causes skin irritation” according to Regulation (EC) No 1272/2008, and as Xi, R38 “Irritating to skin” according to Directive 67/548/EEC. The substance is classified for skin sensitisation as Category 1A, H317 “May cause an allergic skin reaction” according to Regulation (EC) No 1272/2008 and as Xi, R43 “May cause sensitisation by skin contact” according to Directive 67/548/EEC. According to ECHA CSA Guidance Part E Table E3-1, “ low” hazard is assigned in respect of the skin irritation potential of the substance, however, on account of its skin sensitisation potential, “high” hazard is assigned overall in respect of both endpoints.

A qualitative risk characterisation is required in respect of the local inhalation and dermal effects of the substance.

Systemic effects

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore DNELs for acute systemic effects are not proposed.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 1000 mg/kg bw/day from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 1000 mg/kg bw/day x (50/50) = 1000 mg/kg bw/day.

The use of assessment factors according to REACH guidance is considered below:

Interspecies: default values of 4 (allometric scaling: rat) and 2.5 (remaining differences) are proposed.

Intraspecies: a default value of 5 is proposed for workers

Exposure duration: a default value of 6 is proposed for extrapolation from a sub-acute study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default value of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default factor of 1 is proposed

Remaining uncertainties: no analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

An overall assessment factor of 900 for long-term dermal effects is therefore calculated for workers.

Applying the assessment factor of 900 to the dermal equivalent NOAEL of 1000 mg/kg bw/day gives a dermal DNEL value of 1.1 mg/kg bw/day for long-term systemic effects.

[Inhalation – long-term systemic DNEL]

A long-term systemic inhalation DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that the oral absorption rate is 50% that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for workers is derived as: oral NOAEL x (1/0.38 m³/kg/day) x (6.7 m³/10m³(8 h)) x (% oral absorption/ % inhalation absorption) = 1000 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 881.6 mg/m³

The use of assessment factors according to REACH guidance is considered below:

Interspecies: a default factor of 2.5 (remaining differences) is proposed (the application of a factor for allometric scaling is not required for the inhalation route).

Intraspecies: a default factor of 5 is proposed for workers.

Exposure duration: a default factor of 6 is proposed for extrapolation from a sub-acute study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default factor of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default factor of 1 is proposed

Remaining uncertainties: no analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

An overall assessment factor of 225 for long-term inhalational effects is therefore calculated for workers.

Applying the assessment factor of 225 to the corrected inhalation NOAEC of 881.6 mg/m³gives an inhalation DNEL value of 3.9 mg/m³for long-term systemic effects.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.97 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

450

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

A long-term systemic inhalation DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that the oral absorption rate is 50% that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for the general population is derived as: oral NOAEL x (1/1.15 m3/kg/day) x (% oral absorption/ % inhalation absorption) = 1000 mg/kg bw/day x (1/1.15) x (50/100) = 434.8 mg/m3.

AF for dose response relationship:

1

Justification:

Default factor : based on the available data, the substance is of low toxicity

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolation from a sub-acute study to chronic exposure.

AF for other interspecies differences:

2.5

Justification:

Default factor (remaining differences)

AF for intraspecies differences:

10

Justification:

Default factor for the general population

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

3

Justification:

No analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.56 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 800

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A long-term systemic dermal DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 1000 mg/kg bw/day x (50/50) = 1000 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

Default factor: based on the available data, the substance is of low toxicity

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolation from a sub-acute study to chronic exposure.

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor (allometric scaling: rat)

AF for other interspecies differences:

2.5

Justification:

Default factor (remaining differences)

AF for intraspecies differences:

10

Justification:

Default factor for the general population

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

3

Justification:

No analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.56 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 800

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default factor: based on the available data, the substance is of low toxicity

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolation from a sub-acute study to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor (allometric scaling;rat)

AF for other interspecies differences:

2.5

Justification:

Default factor (remaining differences)

AF for intraspecies differences:

10

Justification:

Default factor (for the general population

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

3

Justification:

No analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL derivation [General Population]

Based on the data available, the substance is of low acute toxicity, is not mutagenic, does not cause target organ or systemic toxicity and is not a developmental or reproductive toxin. The substance is irritating to the skin and the eyes and is a skin sensitiser. Classification in respect of these effects is proposed.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 1000 mg/kg bw/day from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422 using the read-across substance: Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine.

Local effects

DNEL values for local inhalation effects are not derived. No data are available regarding local respiratory effects. Since the substance is irritating to the skin and the eyes, local inhalation effects following acute or repeated exposures would be manifested by respiratory irritation. Due to the very low vapour pressure of the substance, inhalation exposures would only be possible in the form of aerosol, consisting of larger droplets depositing in the upper airways which could result in local irritation. However, as no dose-response data regarding local respiratory effects are available, a quantitative dose descriptor (e.g. a DNEL) cannot be calculated based on available information. The absence of route specific information is justified based on conditions of use and qualitative risk characterisation.

DNEL values for local dermal effects are not derived. The substance is irritating and sensitising to the skin. The substance is classified for skin irritation as: Category 2, H315 “Causes skin irritation” according to Regulation (EC) No 1272/2008, and as Xi, R38 “Irritating to skin” according to Directive 67/548/EEC. The substance is classified for skin sensitisation as Category 1A, H317 “May cause an allergic skin reaction” according to Regulation (EC) No 1272/2008 and as Xi, R43 “May cause sensitisation by skin contact” according to Directive 67/548/EEC. According to ECHA CSA Guidance Part E Table E3-1, “ low” hazard is assigned in respect of the skin irritation potential of the substance, however, on account of its skin sensitisation potential, “high” hazard is assigned overall in respect of both endpoints.

A qualitative risk characterisation is required in respect of the local inhalation and dermal effects of the substance.

Systemic effects

The substance is of low systemic toxicity. No acute toxicity hazard resulting in classification has been identified, therefore DNELs for acute systemic effects are not proposed.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 1000 mg/kg bw/day from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that dermal absorption will not exceed oral absorption (i.e. oral and dermal absorption values of 50% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 1000 mg/kg bw/day x (50/50) = 1000 mg/kg bw/day.

The use of assessment factors according to REACH guidance is considered below:

Interspecies: default factors of 4 (allometric scaling: rat) and 2.5 (remaining differences) are proposed.

Intraspecies: a default factor of 10 is proposed (default for the general population)

Exposure duration: a default factor of 6 is proposed for extrapolation from a sub-acute study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default factor of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default factor of 1 is proposed

Remaining uncertainties: no analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

An overall assessment factor of 1800 for long-term dermal effects is therefore calculated for the general population

Applying the assessment factor of 1800 to the dermal equivalent NOAEL of 1000 mg/kg bw/d gives a dermal DNEL value of 0.56 mg/kg bw/d for long-term systemic effects.

[Inhalation – long-term systemic DNEL]

A long-term systemic inhalation DNEL is derived from the oral NOAEL of 1000 mg/kg bw/day using the route-to-route extrapolation approach and default assumptions given in the REACH guidance. It is assumed that the oral absorption rate is 50% that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 50% and 100% respectively are assumed). The corrected inhalation NOAEC for the general population is derived as: oral NOAEL x (1/1.15 m³/kg/day) x (% oral absorption/ % inhalation absorption) = 1000 mg/kg bw/day x (1/1.15) x (50/100) = 434.8 mg/m³

The use of assessment factors according to REACH guidance is considered below:

Interspecies: a default factor of 2.5 (remaining differences) is proposed (the application of a factor for allometric scaling is not required for the inhalation route).

Intraspecies: a default factor of 10 is proposed (default for the general population)

Exposure duration: a default factor of 6 is proposed for extrapolation from a sub-acute study to chronic exposure. This represents a conservative approach, as the data indicate low toxicity following single and repeated exposures

Dose-response: a default factor of 1 is proposed as, based on the available data, the substance is of low toxicity

Quality of the data base: a default factor of 1 is proposed

Remaining uncertainties: no analytical concentration verification was obtained in the study; a factor of 3 is proposed to account for any associated uncertainties.

An overall assessment factor of 450 for long-term inhalational effects is therefore calculated for the general population.

Applying the assessment factor of 450 to the corrected inhalation NOAEC of 434.8 mg/m³gives an inhalation DNEL value of 0.97 mg/m³for long-term systemic effects.

[Oral – long-term systemic DNEL]

Applying the assessment factor of 1800 to the oral NOAEL of 1000 mg/kg bw/d gives an oral DNEL of 0.56 mg/kg bw/day.