Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.93 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

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:

123.3 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the oral subchronic repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalation.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

2

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)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic irritation threshold, see below

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic irritation threshold, see below

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.4 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):

100

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

140 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long term studies with dermal exposure are not available. The long term systemic DNEL for dermal exposure has been derived from the oral subchronic repeated dose toxicity study.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

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)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Selection of the relevant dose descriptors:

NOAEL(repeated dose toxicity) >/= 100 mg/kg bw/d

NOAEL(reproduction/fertility) = 125 mg/kg bw/d

NOAEL(developmental toxicity)>/= 500 mg/kg bw/d

Modification of the relevant dose descriptors to the correct starting point:

Oral absorption

The physicochemical properties of the substance are at least partially favourable for absorption (molecular weight < 500 g/mol, but weighted mean calculated log Kow >4). The longer chain di- and trialkyl compounds are probably absorbed to a lesser extent. The substance is quaternised, which is disadvantageous for the diffusion across the biological membranes in the gastro-intestinal tract. In general, solids with a microscale particle diameter are too large to be directly taken up by pinocytosis and have to be dissolved before they can be absorbed. The target and source substances have a similarly low water solubility, which is likely to reduce absorption.

Based on the available experimental data and on physicochemical properties, a low bioavailability after oral administration can be assumed. For chemical safety assessment, a value of 10% is considered appropriate.

Dermal absorption

The physicochemical properties of the substance are at least partially favourable for absorption (molecular weight < 500 g/mol, but weighted mean calculated log Kow >4). Taking into account the ionic nature of the substances (quaternary ammonium ions) a high dermal absorption is nevertheless unlikely. For chemical safety assessment, a value of 10% is considered appropriate.

Respiratory absorption

The substance is solid at room temperature and has a low vapour pressure (<1E-05 Pa) therefore substance evaporation and uptake by inhalation as vapour is unlikely.

The extent of inhalation absorption deduced from the physico-chemical properties and from the results of oral absorption studies are expected to be low. Furthermore, Di-C12-18 alkyldimethyl ammonium chloride is a quaternised ammonium compound, and the inhalation absorption of ionic substances is generally low. For chemical safety assessment, a value of 20% is considered appropriate taking into account the default correction factor for route-to-route extrapolation from oral to inhalation (Guidance on Information Requirements and Chemical Safety Assessment, R8).

DERIVATION OF DNELs

DNELs derived from subchronic repeated dose toxicity NOAEL

Correction for differences in respiratory volume (worker)	2.63
Correction for light activity at work	0.67
Correction for differences between human and experimental exposure conditions (worker)	1.4

Worker-DNEL long-term for inhalation route (systemic): 4.93 mg/m³

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 123.3 mg/m³

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV x exposure

= 100 x 1/0.38 x 50/100 x 6.7/10 x 1.4

The corrected inhalation NOAECworker (8h) is therefore:

= 123.3 mg/m³ (8h-TWA)

Overall Assessment Factor:25

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:2 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

AF for remaining uncertainties:1 (no remaining uncertainties)

This DNEL does not address the potential for local irritation.Based on the generic irritation threshold as evaluated in the publication “An approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances as a pragmatic tool to fulfill REACH requirements” (Messinger H, 2014.Regulatory Toxicology and Pharmacology 68 (2014) 317–324), the inhalation DNEL was set at 1 mg/m³.The substance is classified as Category 1 (Corrosive).

Worker-DNEL long-term for dermal route (systemic): 1.4 mg/kg bw/d

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 140 mg/kg bw/d

Overall Assessment Factor:100

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:2 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

AF for remaining uncertainties:1 (no remaining uncertainties)

This DNEL does not address the potential for local irritation. The risk characterisation will consider whether specific risk management measures are necessary to protect against local effects.

DNELs derived from the reproduction/fertility NOAEL to dams and offspring (OECD guideline 421)

Correction for differences in respiratory volume (worker)	2.63
Correction for light activity at work	0.67
Correction for differences between human and experimental exposure conditions (worker)	1.4

For (female) fertility effects no assessment factor for time extrapolation was applied as the exposure regime in the screening study is similar to that in the definitive test (1-generation study) from which no time extrapolation would be required – 14 d exposure prior to mating, during pregnancy, lactation, up to weaning (the latter is not relevant in the screening test). No effects to male fertility were observed in this study.

Worker-DNEL long-term for inhalation route (systemic): 12.34 mg/m³

Start value: 125 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 154.2 mg/m³

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV x exposure

= 125 x 1/0.38 x 50/100 x 6.7/10 x 1.4

The corrected inhalation NOAECworker (8h) is therefore:

= 154.2 mg/m³ (8h-TWA)

Overall Assessment Factor:12.5

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required)

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

AF for remaining uncertainties:1 (no remaining uncertainties)

Worker-DNEL long-term for dermal route (systemic): 3.5 mg/kg bw/d

Start value: 125 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 175 mg/kg bw/d

Overall Assessment Factor:50

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required)

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

AF for remaining uncertainties:1 (no remaining uncertainties)

DNELs derived from the developmental NOAEL (prenatal developmental toxicity)

Correction for differences in respiratory volume (worker)	2.63
Correction for light activity at work	0.67
Correction for differences between human and experimental exposure conditions (worker)	1.4

No time extrapolation is required, since the susceptible window is fully covered.

Worker-DNEL long-term for inhalation route (systemic): 49.34 mg/m³

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 616.7 mg/m³

For workers the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x sRVhuman/ wRV x exposure

= 500 x 1/0.38 x 50/100 x 6.7/10 x 1.4

The corrected inhalation NOAECworker (8h) is therefore:

= 616.7 mg/m³ (8h-TWA)

Overall Assessment Factor:12.5

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required)

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

AF for remaining uncertainties:1 (no remaining uncertainties)

Worker-DNEL long-term for dermal route (systemic): 14 mg/kg bw/d

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 700 mg/kg bw/d

Overall Assessment Factor:50

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:1 (no time extrapolation required)

AF for interspecies differences (allometric scaling):4 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:5 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

AF for remaining uncertainties:1 (no remaining uncertainties)

The DNELs for toxicity to reproduction and development are higher than those for repeated dose toxicity. Thus, the repeated dose toxicity-DNELs are also protective for fertility/reproduction.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.74 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

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:

37 mg/m³

Explanation for the modification of the dose descriptor starting point:

Long term inhalation studies are not available. The long term systemic DNEL for inhalation has been derived from the oral subchronic repeated dose toxicity study. For derivation of the dose descriptor starting point a factor of 2 has been included for route-to-route extrapolation from oral to inhalation.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

2

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)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic irritation threshold , see below

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL derivation method:

other: generic irritation threshold, see below

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):

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:

Long term studies with dermal exposure are not available. The long term systemic DNEL for dermal exposure has been derived from the oral subchronic repeated dose toxicity study.

AF for dose response relationship:

1

Justification:

Default (DNEL calculator)

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

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)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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):

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 (DNEL calculator)

AF for differences in duration of exposure:

2

Justification:

Default (DNEL calculator)

AF for interspecies differences (allometric scaling):

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)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Selection of the relevant dose descriptors:

NOAEL(repeated dose toxicity) >/= 100 mg/kg bw/d

NOAEL(reproduction/fertility) = 125 mg/kg bw/d

NOAEL(developmental toxicity)>/= 500 mg/kg bw/d

Modification of the relevant dose descriptors to the correct starting point:

Oral absorption

The physicochemical properties of the substance are at least partially favourable for absorption (molecular weight < 500 g/mol, but weighted mean calculated log Kow >4). The longer chain di- and trialkyl compounds are probably absorbed to a lesser extent. The substance is quaternised, which is disadvantageous for the diffusion across the biological membranes in the gastro-intestinal tract. In general, solids with a microscale particle diameter are too large to be directly taken up by pinocytosis and have to be dissolved before they can be absorbed. The target and source substances have a similarly low water solubility, which is likely to reduce absorption.

Based on the available experimental data and on physicochemical properties, a low bioavailability after oral administration can be assumed. For chemical safety assessment, a value of 10% is considered appropriate.

Dermal absorption

The physicochemical properties of the substance are at least partially favourable for absorption (molecular weight < 500 g/mol, but weighted mean calculated log Kow >4). Taking into account the ionic nature of the substances (quaternary ammonium ions) a high dermal absorption is nevertheless unlikely. For chemical safety assessment, a value of 10% is considered appropriate.

Respiratory absorption

The substance is solid at room temperature and has a low vapour pressure (<1E-05 Pa) therefore substance evaporation and uptake by inhalation as vapour is unlikely.

The extent of inhalation absorption deduced from the physico-chemical properties and from the results of oral absorption studies are expected to be low. Furthermore, Di-C12-18 alkyldimethyl ammonium chloride is a quaternised ammonium compound, and the inhalation absorption of ionic substances is generally low. For chemical safety assessment, a value of 20% is considered appropriate taking into account the default correction factor for route-to-route extrapolation from oral to inhalation (Guidance on Information Requirements and Chemical Safety Assessment, R8).

DERIVATION OF DNELs

DNELs derived from subchronic repeated dose toxicity NOAEL

Correction for differences in respiratory volume (general population)	0.74
Correction for differences between human and experimental exposure conditions (general population)	1

general population-DNEL long-term for inhalation route (systemic): 0.74 mg/m³

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 37 mg/m³

For general population the corrected inhalation NOEC is calculated according to the following equation:

corrected inhalation NOAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ ABSinh-human x exposure

= 100 x 0.74 x 50/100

The corrected inhalation NOAECgeneral population (24h) is therefore:

= 37 mg/m³

Overall Assessment Factor:50

AF for dose response relationship:1 (Default (DNEL calculator))

AF for difference in duration of exposure:2 (Default (DNEL calculator))

AF for interspecies differences (allometric scaling):1 (Default (DNEL calculator))

AF for other interspecies differences:2.5 (Default (DNEL calculator))

AF for intraspecies differences:10 (Default (DNEL calculator))

AF for the quality of the whole database:1 (Default (DNEL calculator))

AF for remaining uncertainties:1 (no remaining uncertainties)

This DNEL does not address the potential for local irritation.Based on the generic irritation threshold as evaluated in the publication “An approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances as a pragmatic tool to fulfill REACH requirements” (Messinger H, 2014.Regulatory Toxicology and Pharmacology 68 (2014) 317–324), the inhalation DNEL was set at 1 mg/m³.The substance is classified as Category 1 (Corrosive).

general population-DNEL long-term for dermal route (systemic): 0.5 mg/kg bw/d

Start value: 100 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 100 mg/kg bw/d

Overall Assessment Factor:200