Amides, tall-oil fatty, N,N-di-Me

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.6 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):

75

Modified dose descriptor starting point:

NOAEC

Value:

44 mg/m³

Explanation for the modification of the dose descriptor starting point:

No studies using inhalation exposure are available. The inhalation DNEL is therefore derived by extrapolation from the NOAEL of 50 mg/kg bw/d from the repeated dose oral toxicity studies. Following correction for breathing rate (/0.38), activity level (*0.67) and the extent of oral absorption (50%, assumed) and inhalation absorption (100%, assumed), an inhalation NOAEC of 44 mg/m3 is derived.

AF for dose response relationship:

1

Justification:

Default value

AF for differences in duration of exposure:

6

Justification:

Extrapolation from sub-acute studies to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Not required (differences already accounted for)

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default value (workers)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No studies using repeated dermal exposure are available. The dermal DNEL is therefore derived by extrapolation from the oral NOAEL of 50 mg/kg bw/d Further correction is not required as the extent of oral and dermal absorption is assumed to be equivalent (worst case assumption)

AF for dose response relationship:

1

Justification:

Default value

AF for differences in duration of exposure:

6

Justification:

Extrapolation from sub-acute studies to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (rat study)

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default value (workers)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

61 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

37.5

Dose descriptor:

other: LOAEL

AF for dose response relationship:

3

Justification:

Use of a LOAEL (EC3 value)

AF for differences in duration of exposure:

1

Justification:

Not relevant for skin sensitisation

AF for interspecies differences (allometric scaling):

1

Justification:

Not relevant for local effects

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

5

Justification:

Default value (workers)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

61 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

37.5

Dose descriptor starting point:

other: LOAEL

AF for dose response relationship:

3

Justification:

Use of a LOAEL (EC3 value)

AF for interspecies differences (allometric scaling):

1

Justification:

Not relevant for skin sensitisation

AF for other interspecies differences:

2.5

Justification:

Not relevant for local effects

AF for intraspecies differences:

5

Justification:

Default value (workers)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Available data relevant to DNEL derivation come from the skin sensitisation study (for local dermal effects) and from the OECD 422 reproductive/developmental toxicity screening study (for systemic effects).

Local dermal DNEL: starting point

An EC3 of 9.13% was calculated in a skin sensitisation study (Local Lymph Node Assay).

Systemic DNELs: starting point

NOAELs of 50 mg/kg bw/d (systemic toxicity, males), 300 mg/kg bw/d (systemic toxicity, females), 50 mg/kg bw/d (reproductive toxicity) and 1000 mg/kg bw/d (developmental toxicity) are derived for the OECD 422 study. An overall oral NOAEL of 50 mg/kg bw/d is therefore used as the starting point.

Inhalation DNEL values

Systemic DNELs

No studies involving inhalation exposure are available. The long-term systemic inhalation DNEL is therefore derived by extrapolation from the oral NOAEL of 50 mg/kg bw/d.  Following correction for breathing rate (/0.38), activity level (*0.67) and the extent of oral absorption (50%, assumed) and inhalation absorption (100%, assumed), a corrected inhalation NOAEC of 44 mg/m3 was derived. Individual Assessment Factors of 1 (for dose-response relationship), 6 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties) result in an overall Assessment Factor of 75. Applying the overall Assessment Factor to the modified starting point results in a long-term systemic inhalation DNEL of 0.6 mg/m3.

A short-term systemic inhalation DNEL is not derived in the absence of any identified hazard, based on low vapour and consequently low likelihood of exposure.

Local DNELs

Local inhalation DNELs are not derived in the absence of any identified hazard. No classification of Amides, tall-oil fatty, N,N-di-Methyl (DMATO) was appropriate for acute oral, dermal or inhalation toxicity.

Dermal DNEL values

Systemic DNELs

No studies using repeated dermal exposure are available. The long-term systemic dermal DNEL is therefore derived by extrapolation from the oral NOAEL of 50 mg/kg bw/d.

Further correction is not required as the extent of oral and dermal absorption is assumed to be equivalent, as a worst case.  Individual Assessment Factors of 1 (for dose-response relationship), 6 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties) result in an overall Assessment Factor of 300. Applying the overall Assessment Factor to the starting point results in a long-term systemic DNEL of 0.2 mg/kg bw/d.

A short-term systemic dermal DNEL is not derived in the absence of any identified hazard. No classification was necessary for dermal toxicity.

Local DNELs

The substance is identified as a potential skin sensitiser in a mouse LLNA (EC3 = 9.13%; 2282.5 µg/cm²). Individual Assessment Factors of 3 (for dose-response relationship; the EC3 is considered equivalent to the LOAEL), 1 (for exposure duration, not relevant for sensitisation), 1 (for allometric scaling, not relevant for local effects), 2.5 (for other interspecies differences), 5 (for intraspecies differences: workers) and 1 (for database quality) result in an overall Assessment Factor of 37.5. Applying the overall Assessment Factor to the LOAEL results in a local dermal DNEL for sensitisation of 61 µg/cm2.

Identification of respiratory sensitisers is important due to the health concerns associated occupational asthma but there are no accepted regulatory models currently capable of assessing the potential for induction of respiratory sensitisation/allergy. Various models are available for assessing the potential for induction of allergic contact dermatitis (ACD), for example the Local Lymph Node Assay, but Dearman and Kimber have reported that only a small number of compounds that give positive LLNA responses are actually respiratory sensitisers. There are important mechanistic differences in the aetiology of ACD and respiratory allergy. Respiratory allergic responses are classified as Type I hypersensitivity mediated by IgE whereas ACD is a Type IV hypersensitivity mediated by T cells. ACD involves T helper cells of one subpopulation, involving interleukin-2, interferon-gamma and tumour necrosis factor beta (TNF-ß); respiratory allergy is associated with the Th2 T helper cells of a second subpopulation associated with production of Interleukins 4, 10 and 13; these cytokines tend to favour humoral immune function and stimulation of B cells to produce IgE. The activities of inflammatory mediators and Th2 cytokines may result in respiratory allergy including effects in mast cells and eosinophils. Dearman and Kimber 1999 and Arts and Kuper 2007 have investigated the use of LLNA models to assess the respiratory allergenicity of compounds using mice in a sensitised state following dermal or respiratory contact. Both allergic states involve proliferative responses but the resultant T-cell populations and effective pathways are different for contact and respiratory sensitisers. Only a small number of potentially contact sensitising substances have respiratory allergic effects, typically low molecular weight substances capable of forming haptens. In the absence of validated IgE or pulmonary response assays to determine respiratory sensitising potential, the identification of a respiratory allergen is largely dependent on human evidence and direct correlation between contact and respiratory sensitising substances can be drawn from the results of the LLNA test in isolation.

Given that DMATO shows no evidence of inflammatory or irritant responses, it cannot be concluded that any respiratory allergic hazard is indicated by the positive contact sensitising response in the LLNA study summary.

Toxicology and Applied Pharmacology 226 (2008) 1 -13. D R Boverhof et al.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 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):

150

Modified dose descriptor starting point:

NOAEC

Value:

22 mg/m³

Explanation for the modification of the dose descriptor starting point:

No studies using inhalation exposure are available. The inhalation DNEL is therefore derived by extrapolation from the oral NOAEL of 50 mg/kg bw/d. Following correction for breathing rate (/1.15) and the extent of oral absorption (50%, assumed) and inhalation absorption (100%, assumed), a corrected inhalation NOAEC of 22 mg/m3 is derived.

AF for dose response relationship:

1

Justification:

Default value

AF for differences in duration of exposure:

6

Justification:

Extrapolation from sub-acute studies to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Not required (differences already accounted for)

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value (general population)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No studies of repeated toxicity using dermal exposure are available. The dermal DNEL is therefore derived by extrapolation from the oral NOAEL of 50 mg/kg bw/d. Further correction is not required as the extent of oral and dermal absorption is assumed to be equivalent (worst case assumption)

AF for dose response relationship:

1

Justification:

Default value

AF for differences in duration of exposure:

6

Justification:

Extrapolation from sub-acute studies to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (rat study)

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value (general population)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

30 µg/cm²

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor:

other: LOAEL

AF for dose response relationship:

3

Justification:

Use of a LOAEL (EC3 value)

AF for differences in duration of exposure:

1

Justification:

Not relevant for skin sensitisation

AF for interspecies differences (allometric scaling):

1

Justification:

Not relevant for local effects

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value (general population)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

30 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

other: LOAEL

AF for dose response relationship:

3

Justification:

Use of a LOAEL (EC3 value)

AF for interspecies differences (allometric scaling):

1

Justification:

Not relevant for local effects

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value (general population)

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.1 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):

600

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The oral DNEL is derived from the oral NOAEL of 50 mg/kg bw/d. Further correction is not required.

AF for dose response relationship:

1

Justification:

Default value

AF for differences in duration of exposure:

6

Justification:

Extrapolation from sub-acute studies to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

Default value (rat study)

AF for other interspecies differences:

2.5

Justification:

Default value

AF for intraspecies differences:

10

Justification:

Default value

AF for the quality of the whole database:

1

Justification:

Default value

AF for remaining uncertainties:

1

Justification:

Default value

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Available data relevant to DNEL derivation come from the skin sensitisation study (for local dermal effects) and from the OECD 422 reproductive/developmental toxicity screening study (for systemic effects).

Local dermal DNEL: starting point

An EC3 of 9.13% was calculated in a skin sensitisation study (Local Lymph Node Assay).

Systemic DNELs: starting point

NOAELs of 50 mg/kg bw/d (systemic toxicity, males), 300 mg/kg bw/d (systemic toxicity, females), 50 mg/kg bw/d (reproductive toxicity) and 1000 mg/kg bw/d (developmental toxicity) are derived for the OECD 422 study. An overall oral NOAEL of 50 mg/kg bw/d is therefore used as the starting points.

Inhalation DNEL values

Systemic DNELs

No studies involving inhalation exposure are available. The long-term systemic inhalation DNEL is therefore derived by extrapolation from the oral NOAEL of 50 mg/kg bw/d. Following correction for breathing rate (1/1.15) and the extent of oral absorption (50%, assumed) and inhalation absorption (100%, assumed), a corrected inhalation NOAEC of 22 mg/m³was derived. Individual Assessment Factors of 1 (for dose-response relationship), 6 (for duration of exposure), 1 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties) result in an overall Assessment Factor of 150. Applying the overall Assessment Factor to the modified starting point results in a long-term systemic inhalation DNEL of 0.15 mg/m³.

A short-term systemic inhalation DNEL is not derived in the absence of any identified hazard.

Local DNELs

Local inhalation DNELs are not derived in the absence of any identified hazard. No classification of Amides, tall-oil fatty, N,N-di-Methyl (DMATO) was appropriate for acute oral, dermal or inhalation toxicity.

 

Dermal DNEL values

Systemic DNELs

No studies using repeated dermal exposure are available. The long-term systemic dermal DNEL is therefore derived by extrapolation from the oral NOAEL of 50 mg/kg bw/d.

Further correction is not required as the extent of oral and dermal absorption is assumed to be equivalent (worst case assumption). Individual Assessment Factors of 1 (for dose-response relationship), 6 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 5 (for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties) result in an overall Assessment Factor of 600. Applying the overall Assessment Factor to the starting point results in a long-term systemic DNEL of 0.1 mg/kg bw/d.

A short-term systemic dermal DNEL is not derived in the absence of any identified hazard. No classification was necessary for dermal toxicity.

Local DNELs

The substance is identified as a potential skin sensitiser in a mouse LLNA (EC3 = 9.13%; 2282.5 µg/cm²). Individual Assessment Factors of 3 (for dose-response relationship; the EC3 is considered equivalent to the LOAEL), 1 (for exposure duration, not relevant for sensitisation), 1 (for allometric scaling, not relevant for local effects), 2.5 (for other interspecies differences), 5 (for intraspecies differences: workers) and 2 (for database quality) result in an overall Assessment Factor of 37.5. Applying the overall Assessment Factor to the LOAEL results in a local dermal DNEL for sensitisation of 61 µg/cm².

 

Oral DNEL values

Systemic DNELs

The long-term systemic oral DNEL is derived from the overall NOAEL of 50 mg/kg bw/d.  Further correction is not required.  Individual Assessment Factors of 1 (for dose-response relationship), 6 (for duration of exposure), 4 (for allometric scaling), 2.5 (for other interspecies differences), 10 (for intraspecies differences, 1 (for database quality) and 1 (for remaining uncertainties) result in an overall Assessment Factor of 600. Applying the overall Assessment Factor to the starting point, results in a long-term systemic oral DNEL of 0.1 mg/kg bw/day.

A short-term systemic oral DNEL is not derived in the absence of any identified hazard.