Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.05 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):
25
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
176.3 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 100 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 similarly low to that of the inhalation rate (i.e. oral and inhalation absorption values of both 10% 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) = 100 mg/kg bw/day x (1/0.38) x 0.67 x (10/10) = 176.3 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:
2
Justification:
A default factor for extrapolation from a sub-chronic study to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable
AF for other interspecies differences:
2.5
Justification:
A default factor (remaining difference)
AF for intraspecies differences:
5
Justification:
A default factor for workers
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 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 100 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 10% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 100 mg/kg bw/day x (10/10) = 100 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:
2
Justification:
A default factor for extrapolation from a sub-chronic 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:
A default factor for workers
AF for the quality of the whole database:
1
Justification:
Default factor
AF for remaining uncertainties:
1
Justification:
Default factor
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)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

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, C16 and C18 unsatd., polymers with bisphenol A, Butyl glycidyl ether, epichlorohydrin and triethylenetetramine

 

Toxicokinetics

Based on physicochemical data, toxicity data and theoretical assessment, the basic toxicokinetics of fatty acids, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether 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, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether and triethylenetetramine is of low acute oral and dermal toxicity: The LD50 via 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, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether and triethylenetetramine was found to be irritating to skin, but not corrosive, in in vitro studies 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 an in vitro BCOP assay, it was severely irritating to the eyes in a study in 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, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether 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, a component and starting material of fatty acids, tall-oil, reaction product with bisphenol A, epichlorohydrin, glycidyl tolyl ether 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).

The 90-day oral repeated dose toxicity study in the rat (OECD Test Guideline 408) is proposed to further characterise the repeated dose toxicity of fatty acids, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether and triethylenetetramine.

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, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether and triethylenetetramine in a bacterial reverse mutation assay (Ames test). Negative results were obtained in in vitro mammalian cytogenicity and gene mutation studies. The substance is not genotoxic in vitro in bacterial or in mammalian cell systems. 

Toxicity to reproduction

No evidence of an effect on the reproductive organs was seen in a combined repeated dose and reproductive/developmental screening study (OECD 422) in rats after repeated oral doses up to 1000 mg/kg bw/day. The findings from a proposed 90-day repeated dose oral toxicity study (OECD 408) and a pre-natal developmental toxicity study (OECD 414) will provide a further characterisation of the reproductive hazard potential of Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine.

The 90-day repeated dose oral toxicity study was designed to investigate the systemic toxicity of the test item and is compatible with the following regulatory guidelines:

The OECD Guidelines for Testing of Chemicals No. 408 "Subchronic Oral Toxicity - Rodent: 90 Day Study” (Adopted 21 September 1998).

This study was also designed to be compatible with Commission Regulation (EC) No 440/2008 of 30 May 2008, laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

The test item was administered by oral gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at intended dosages of 100, 300 and 1000 mg/kg bw/day over a period of ninety consecutive days. After review of Week 1 data, it was considered that the high dosage of 1000 mg/kg bw/day was too high and this was reduced to 600 mg/kg bw/day from Day 12 for males and Day 13 for females. This dosage was further reduced to 450 mg/kg bw/day from Day 21 for males and Day 20 for females due to poor body weight performance and mortality during Week 3. A control group of males and females was dosed with the vehicle alone (PEG 400) using a constant dose volume of 4 ml/kg over the same treatment period. Clinical signs, functional observations, body weight change, dietary intake and water consumption were monitored during the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Ophthalmoscopy examination was also performed on control group and high dose animals. All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues from high dose and control animals was performed. This was extended to include low and intermediate dose animals for the mesenteric lymph nodes.

Based on the results of this study, the No Observed Adverse Effect Level for the rat following 90 consecutive days of treatment with TOFA_TETA_PAA_BADGE_CGE was considered to be 100 mg/kg bw/day.

 

The pre-natal developmental toxicity study was performed to investigate the effects of the test item on embryonic and fetal development following repeated administration by gavage to the pregnant female rat during gestation including the period of organogenesis.

The study was designed to comply with the following guidelines:

US EPA Health Effects Test Guideline OPPTS 870.3700, ‘Prenatal Developmental Toxicity Study’ (August 1998)

Japanese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147, (24 November 2000)

OECD Guidelines for Testing of Chemicals, No 414, ‘Prenatal Developmental Toxicity Study’ (adopted 22 January 2001)

Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to Regulations (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)

The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, between Days 5 and 19 of gestation inclusive at dose levels 100, 300, and 1000 mg/kg bw/day. Due to adverse maternal toxicity, the high dosage was subsequently lowered to 600 mg/kg bw/day and then to 450 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Polyethylene Glycol 400) to serve as a control.

Clinical signs, body weight change, food and water consumptions were monitored during the study. All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, fetal weight, sex and external and internal macroscopic appearance were recorded. Approximately half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.

Based on this study the No Observed Effect Level (NOEL) for the pregnant female rat was considered to be 100 mg/kg bw/day. A maternal dosage of at least 450 mg/kg bw/day was therefore considered to be the No Observed Effect Level (NOEL) for the growth survival and development of the offspring.

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 in the combined 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. The assumption of limited bioavailability will be reassessed, once the proposed OECD 414 study is available.

 

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 100 mg/kg bw/day from an OECD 408 Subchronic 90 day Oral Toxicity rat study conducted in rats.

 

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 100 mg/kg bw/day from a 90 day repeated dose toxicity study conducted in rats according to OECD Test Guideline 408, using the registered test substance.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 100 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 10% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 100 mg/kg bw/day x (10/10) = 100 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 2 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: a default factor of 1 is proposed. 

An overall assessment factor of 100 for long-term dermal effects is therefore calculated for workers.

Applying the assessment factor of 100 to the dermal equivalent NOAEL of 100 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 100 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 10% as that of the inhalation absorption rate (i.e. oral and inhalation absorption values of 10% 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) = 100 mg/kg bw/day x (1/0.38) x 0.67 x (10/10) = 176.3 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 2 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: a default factor of 1 is proposed. 

An overall assessment factor of 25 for long-term inhalational effects is therefore calculated for workers.

Applying the assessment factor of 25 to the corrected inhalation NOAEC of 176.3 mg/m3 gives an inhalation DNEL value of 7.05 mg/m3 for long-term systemic effects.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.74 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
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
87 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 100 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 10% as is the inhalation absorption rate (i.e. oral and inhalation absorption values of 10% and 10% 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) = 100 mg/kg bw/day x (1/1.15) x (10/10) = 87.0 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:
2
Justification:
Default factor for extrapolation from a sub-chronic study to chronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable
AF for other interspecies differences:
2.5
Justification:
Default factor (remaining difference)
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
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 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 100 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 10% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 100 mg/kg bw/day x (10/10) = 100 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:
2
Justification:
Default factor for extrapolation from a sub-chronic 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:
1
Justification:
Default factor
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)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
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 related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 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:
2
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:
1
Justification:
Default factor
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

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 100 mg/kg bw/day from a c from a sub-chronic 90-day oral toxicity study in rats (OECD 408). with Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine, a component and starting material of fatty acids, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether 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 100 mg/kg bw/day from a from a sub-chronic 90-day oral toxicity study in rats (OECD 408) with Fatty acids, C18-unsatd., dimers, oligomeric reaction products with tall-oil fatty acids and triethylenetetramine, a component and starting material of fatty acids, tall-oil, reaction products with bisphenol A, epichlorohydrin, glycidyl tolyl ether and triethylenetetramine.

[Dermal – long-term systemic DNEL]

A long-term systemic dermal DNEL is derived from the oral NOAEL of 100 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 10% respectively are assumed). The equivalent dermal NOAEL is derived as: oral NOAEL x (% oral absorption/ % dermal absorption) = 100 mg/kg bw/day x (10/10) = 100 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 2 is proposed for extrapolation from a sub-chronic 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: a default factor of 1 is proposed. 

An overall assessment factor of 600 for long-term dermal effects is therefore calculated for the general population

Applying the assessment factor of 600 to the dermal equivalent NOAEL of 1000 mg/kg bw/d gives a dermal DNEL value of 1.67 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 100 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 10% as is the inhalation absorption rate (i.e. oral and inhalation absorption values of 10% and 10% 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) = 100 mg/kg bw/day x (1/1.15) x (10/10) = 87.0 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 2 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: a default factor of 1 is proposed. 

An overall assessment factor of 50 for long-term inhalational effects is therefore calculated for the general population.

Applying the assessment factor of 50 to the corrected inhalation NOAEC of 87.0 mg/m3gives an inhalation DNEL value of 1.74 mg/m3for long-term systemic effects.

[Oral – long-term systemic DNEL]

Applying the assessment factor of 200 to the oral NOAEL of 100 mg/kg bw/d gives an oral DNEL of 0.5 mg/kg bw/day.