Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

264.5 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 300 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) = 300 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 264.5mg/m3.

AF for dose response relationship:

1

Justification:

Default factor

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolating from subacute to chronic exposures

AF for interspecies differences (allometric scaling):

1

Justification:

Not required

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:

1

Justification:

Default factor

Hazard assessment conclusion:

low hazard (no threshold derived)

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 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):

300

Modified dose descriptor starting point:

NOAEL

Value:

300 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 300 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) = 300 mg/kg bw/day x (50/50) = 300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default factor

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolating from subacute to chronic exposures

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor

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:

1

Justification:

Default factor

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

high hazard (no threshold derived)

Hazard assessment conclusion:

high hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Identity of the substance and approach to meeting the data requirements

Fatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts

Toxicokinetics

No specific studies are available however based on physicochemical data, toxicity data and theoretical assessment, the basic toxicokinetics of Fatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts can be adequately characterised. No absorption of the intact substance via the oral, dermal or inhalation routes is predicted. Consideration of distribution, metabolism and excretion is not therefore relevant. In the absence of systemic bioavailability, bioaccumulation is not predicted.

Acute toxicity

The acute oral LD₅₀ofFatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts was determined to be >500 mg/kg bw in an acute oral toxicity study conducted in rats according to OECD Guideline 423. Based on existing datasets and structural and chemical considerations, read-across fromFatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate saltsto an acute dermalstudy on Fatty acid C18 unsat reaction products with diethylenetriamine, acetate salts is appropriate to meet the REACH Annex VII-IX data requirements. In the key study conducted in accordance with OECD Test Guideline 402, the acute dermal toxicity of Fatty acid C18 unsat reaction products with diethylenetriamine, acetate salts was found to be low; the acute dermal LD₅₀was > 2000 mg/kg bw/day (Sanders, 2012). 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 route and acute dermal toxicity is predicted to be low. Inhalation is not predicted to be a significant route of exposure based on the physicochemical properties and use pattern of the substance.

Irritation/corrosion

Based on existing datasets and structural and chemical considerations, read-across fromFatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate saltsto skin and eyeirritation studies using Fatty acid C18 unsat, reaction products with diethylenetriamine, acetate salts is appropriate to meet the REACH Annex VII-IX data requirements. Based on read-across toin vivoskin and eye irritation/corrosion studies conducted according to OECD Test Guidelines 404 and 405 respectively using Fatty acid C18 unsat reaction products with diethylenetriamine, acetate salts,Fatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts is predicted to be irritating to the skin and corrosive to eyes.

Skin sensitisation

Based on existing datasets and structural and chemical considerations, read-across fromFatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate saltsto a skin sensitisationstudy on Fatty acid C18 unsat reaction products with diethylenetriamine, acetate salts is appropriate to meet the REACH Annex VII-IX data requirements. Fatty acid C18 unsat reaction products with diethylenetriamine, acetate salts was found to be a skin sensitiser in a study conducted according to OECD Test Guideline 406;Fatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts is similarly predicted to be a skin sensitiser.

Repeated dose toxicity

Read-across to the findings of a sub-acute repeated dose study conducted according to OECD Test Guideline 422 usingFatty acids C18 unsat, reaction products with pentaethylenehexamineis considered appropriate to characterise the repeated dose toxicity of the substance and meet the REACH Annex VII-IX data requirements. In the key study conducted in accordance with OECD Test Guideline 422, the NOAEL for sub-acute repeated dose toxicity was 300 mg/kg bw/day (i.e. the highest dose tested).

Genetic toxicity

No evidence of mutagenicity was seen forFatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts in a bacteria reverse mutation assay (Ames test) conducted according to OECD Test Guideline 471.

Based on existing datasets and structural and chemical considerations, read-across fromFatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts to genotoxicity studies using Fatty acid C18 unsat reaction products with diethylenetriamine is appropriate to meet the REACH Annex VII-IX data requirements. Based on read-across to negative results obtained inin vitromammalian cytogenicity and gene mutation studies using, Fatty acid C18 unsat reaction products with diethylenetriamine, Fatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts is not predicted to be genotoxic in mammalian cell systems in vitro.

Toxicity to reproduction

Based on read-across to the results of a combined repeated dose/reproductive toxicity study (OECD Test Guideline 422) usingFatty acids C18 unsat, reaction products with pentaethylenehexamine, the substance: Fatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts is not predicted to cause reproductive toxicity. In the study, no effects on reproductive parameters were observed at doses up to 300 mg/kg bw/day (i.e. the highest dose tested). The reproductive toxicity hazard of the substance will be further characterised based on read-across to the findings from planned 90-day repeated dose oral toxicity (OECD Test Guideline 408) and pre-natal developmental toxicity (OECD Test Guideline 414) studies using Fatty acid C18 unsat reaction products with diethylenetriamine.

DNEL derivation [Workers]

Based on the data available, the substance 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 acute oral LD₅₀of the substance was determined to be 500 mg/kg bw/day; the substance meets the criteria for classification for acute oral toxicity as Risk Phrase R22 “Harmful if swallowed” according to Directive 67/548/EEC and Category 4 H302 “Harmful if swallowed” according to Regulation 1272/2008/EC.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 300 mg/kg bw/day, based on read-across from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422 using the substance:Fatty acids C18 unsat, reaction products with pentaethylenehexamine.

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 this endpoint.

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

Systemic effects

The acute oral LD₅₀of the substance was determined to be 500 mg/kg bw/day; the substance meets the criteria for classification for acute oral toxicity as Risk Phrase R22 “Harmful if swallowed” according to Directive 67/548/EEC and Category 4 H302 “Harmful if swallowed” according to Regulation 1272/2008/EC. The available information on similar substances indicates that these substances have low acute toxicity following oral, dermal and inhalation exposures. There are no data available to determine a DNEL for acute effects; a qualitative approach is required in respect of the acute systemic toxicity of the substance following dermal and inhalation exposures. Taking account the classification of the substance for acute oral toxicity, it is considered to be “low hazard”. Since the substance is irritating to the skin and eyes and a strong skin sensitiser and is considered to be “medium/high” hazard in this respect, the skin and mucus membranes should be protected with appropriate measures. The required measures are expected to be adequately protective towards acute exposures.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 300 mg/kg bw/day, based on read-across from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422 using the substance:Fatty acids C18 unsat, reaction products with pentaethylenehexamine.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 300 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) = 300 mg/kg bw/day x (50/50) = 300 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

An overall assessment factor of 300 for long-term dermal effects is therefore calculated for workers.

Applying the assessment factor of 300 to the dermal equivalent NOAEL of 300 mg/kg bw/day gives a dermal DNEL value of 1.0 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 300 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) = 300 mg/kg bw/day x (1/0.38) x 0.67 x (50/100) = 264.5 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).

Intrapecies: 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

An overall assessment factor of 75 for long-term inhalational effects is therefore calculated for workers.

Applying the assessment factor of 75 to the corrected inhalation NOAEC of 264.5 mg/m³gives an inhalation DNEL value of 3.5 mg/m³for long-term systemic effects.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.87 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

NOAEC

Value:

130.4 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 300 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) = 300 mg/kg bw/day x (1/1.15) x (50/100) = 130.4 mg/m3.

AF for dose response relationship:

1

Justification:

Default factor

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolating from subacute to chronic exposures

AF for interspecies differences (allometric scaling):

1

Justification:

Not required

AF for other interspecies differences:

2.5

Justification:

Default factor (remaining differences)

AF for intraspecies differences:

10

Justification:

Default factor (general population)

AF for the quality of the whole database:

1

Justification:

Default factor

AF for remaining uncertainties:

1

Justification:

Default factor

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

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 derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

AF for dose response relationship:

1

Justification:

Default factor

AF for differences in duration of exposure:

6

Justification:

Default factor for extrapolating from subacute to chronic exposures

AF for interspecies differences (allometric scaling):

4

Justification:

Default factor

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:

1

Justification:

Default factor

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

no hazard identified

DNEL derivation [General Population]

There are no consumer uses ofFatty acids C18 unsat, reaction products with pentaethylenehexamine, acetate salts; the substance is used in industrial and professional settings only. DNELs have however been derived for the consideration of indirect exposures via the environment.

Based on the data available, the substance 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 acute oral LD₅₀of the substance was determined to be 500 mg/kg bw/day; the substance meets the criteria for classification for acute oral toxicity as Risk Phrase R22 “Harmful if swallowed” according to Directive 67/548/EEC and Category 4 H302 “Harmful if swallowed” according to Regulation 1272/2008/EC.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 300 mg/kg bw/day, based on read-across from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422 using the substance:Fatty acids C18 unsat, reaction products with pentaethylenehexamine.

Local effects

There are no consumer uses of the substance; the consideration of local effects is not therefore relevant

Systemic effects

DNELs for long-term effects via the oral and inhalation route are relevant to the assessment of human health effects via the environment.

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 300 mg/kg bw/day, based on read-across from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422 using the substance:Fatty acids C18 unsat, reaction products with pentaethylenehexamine.

[Dermal – long-term systemic DNEL]

Indirect dermal exposures via the environment are not relevant

[Inhalation – long-term systemic DNEL]

A long-term systemic inhalation DNEL is derived from the oral NOAEL of 300 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) = 300 mg/kg bw/day x (1/1.15) x (50/100) = 130.4 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

An overall assessment factor of 150 for long-term inhalational effects is therefore calculated for the general population.

Applying the assessment factor of 150 to the corrected inhalation NOAEC of 130.4 mg/m³gives an inhalation DNEL value of 0.87 mg/m³for long-term systemic effects.

[Oral – long-term systemic DNEL]

The relevant (lowest) NOAEL for general/systemic toxicity for DNEL derivation is the NOAEL of 300 mg/kg bw/day, based on read-across from a combined repeated oral dose and reproductive/developmental screening study conducted in rats according to OECD Test Guideline 422 using the substance:Fatty acids C18 unsat, reaction products with pentaethylenehexamine.

The following assessment factors have been used in accordance with REACH guidance:

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

An overall assessment factor of 600 for long-term effects is therefore calculated for the general population. Applying the assessment factor of 600 to the oral NOAEL of 300 mg/kg bw/d gives an oral DNEL of 0.5 mg/kg bw/day.