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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.952 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Value:
71.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.272 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
180
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Value:
49 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
5
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
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)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Identity of the substance and approach to meeting the data requirements

Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine

 

Toxicokinetics

Based on physicochemical data, toxicity data and theoretical assessment, the basic toxicokinetics of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine 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

 

Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine is of low acute oral and dermal toxicity: the LD50via both routes respectively is > 2000 mg/kg bw. 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, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine was found to be irritating to skin, but not corrosive, inin vitrostudies using the EpiDerm™ skin model (Dreher, 2012a and b), according to OECD Test Guidelines. The substance meets the criteria for classification 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.

In eye irritation studies, while the substance was not irritating in anin vitroBCOP assay, it was severely irritating to the eyes in a studyin vivo. The substance meets the criteria for classification as Category 1, H318 “Causes serious eye damage” according to Regulation (EC) No 1272/2008 and Xi, R41 “Risk of serious damage to eyes” according to Directive 67/548/EEC.

Skin sensitisation

Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine was considered to be a skin sensitiser in the Local Lymph Node Assay (LLNA). 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

 

The sub-acute repeated dose oral toxicity of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine was investigated in rats in a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test conducted according to OECD Test Guideline 422 (Perks, 2013). In the study, no treatment related effects were observed following the administration of the substance by oral gavage at doses up to 1000 mg/kg bw/day. Based on this study, The No-Observed-Adverse-Effect-Level (NOAEL) for the sub-acute repeated dose oral toxicity of the substance in male and female rats was considered to be 1000 mg/kg bw/day (i.e. the highest dose tested).

In the 90-day oral repeated dose toxicity study in the rat (OECD Test Guideline 408) rats were administered the substance at dose levels of 100, 300 and 1000 mg/kg/d for 90 days and then a high dose recovery group were examined following a 28 day recovery phase. The NOAEL for repeated dose toxicity was considered to be 1000 mg/kg bw/d (the highest dose tested).

Waivers are proposed for repeated dose toxicity tests via the inhalation and dermal routes in accordance with Column 2 of Annex VIII of the REACH Regulation. The repeated dose toxicity of the substance will be adequately elucidated by the oral route, with additional testing proposed. Further testing via the dermal and inhalation routes is not required.

 

Genetic toxicity

No evidence of mutagenicity was seen for Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine in a bacterial reverse mutation assay (Ames test). Negative results were obtained inin vitromammalian cytogenicity and gene mutation studies. The substance is not genotoxicin vitroin bacterial or in mammalian cell systems. 

Toxicity to reproduction

 

The effects of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine on fertility and on developmental parameters have been investigated in a combined repeated dose/reproductive screening toxicity study conducted according to OECD Test Guideline 422 (Perks, 2013). No developmental effects, effects on reproductive parameters or treatment-related signs of systemic toxicity were observed in the study. Based on this study, The No-Observed-Adverse-Effect-Level (NOAEL) for the effects of the substance on fertility in male and in female rats and for developmental toxicity was considered to be 1000 mg/kg bw/day (i.e. the highest dose tested).

A pre-natal developmental toxicity study using Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine in the rat (OECD Test Guideline 414) was conducted using dose levels of 100, 300 or 1000 mg/kg bw/d. No signs of developmental toxicity or teratogenicity were observed at doses up to 1000 mg/kg bw/d. The NOAEL for fetal developmental toxicity and teratogenicity was established as 1000 mg/kg bw/d.

In the study conducted with the rabbit, the test item was administered by oral gavae at 15, 35 and 75 mg/kg bw/d. There were no signs of developmental toxicity or teratogenicity in the abscence of maternal toxicity. Maternal toxicity was noted at 35 mg/kg/d but the NOAEL for developmental toxicty was establised as 1000 mg/kg bw/d.

In accordance with Column 2 of Annex X of the REACH regulation, a waiver is proposed for the two-generation reproductive toxicity study. No adverse effects or indication of systemic exposure were observed inthecombined repeated dose toxicity with reproduction/developmental toxicity screening test (OECD 422) at dose levels up to and including the limit dose. Also, according to Lipinski’s Rule of Five, the substance is not predicted to be bioavailable (OECD QSAR Toolbox). No additional testing is therefore considered necessary on scientific grounds and in the interests of avoiding unnecessary animal testing in accordance with EU Directive 86/609/EEC.

 

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 35 mg/kg bw/day from a prenatal developmental toxicity study in the rabbit (OECD 414).

 

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 35 mg/kg bw/day from a prenatal developmental toxicity study in the rabbit (OECD 414).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.169 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Value:
25.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
1
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.2 µg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
360
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Value:
35 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
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)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
97.2 µg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
360
Dose descriptor starting point:
NOAEL
Value:
35 mg/kg bw/day
Value:
35 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Default (DNEL calculator)

AF for dose response relationship:
1
Justification:
Default (DNEL calculator)
AF for differences in duration of exposure:
6
Justification:
Default (DNEL calculator)
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default (DNEL calculator)
AF for other interspecies differences:
2.5
Justification:
Default (DNEL calculator)
AF for intraspecies differences:
10
Justification:
Default (DNEL calculator)
AF for the quality of the whole database:
1
Justification:
Default (DNEL calculator)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

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