Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.21 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
12
Dose descriptor starting point:
NOAEL
Value:
113 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
98.58 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 inhalative.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchonic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known pathways for metabolism involving ubiquitous and non-specific enzyme systems (amidases/esterases,fatty acid metabolism) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
An additional AF of 2 has been included taking account of remaining uncertainties due to read-across.
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:
1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.35 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
Value:
113 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 ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known pathways for metabolism involving ubiquitous and non-specific enzyme systems (amidases/esterases,fatty acid metabolism) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
An additional AF of 2 has been included taking account of remaining uncertainties due to read-across.
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Selection of the relevant dose descriptors:

Oral:

NOAEL =113 mg/kg bw/day: subchronic repeated dose toxicity study, rat, oral (gavage); read-across: Coco alkyl trimethyl ammonium chloride

 

NOAEL(development) = 200 mg/kg; NOAEL(male fertility) = 200 mg/kg bw/d; NOAEL(female fertility) = 70 mg/kg bw/d (reduced number of implantation sites at 200 mg/kg bw/d); read-across: Stearic acid 3-(dimethylaminopropyl)amide 

 

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

Oral absorption

The physicochemical properties of C16 Alkylamidopropyltrimethylammonium Chloride (log Kow = 2.49) and the molecular weight of 391.07 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion (molecular weight < 500 g/mol, log Kow between -1 and 4).

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data

 

Dermal absorption

It is generally thought that ionised substances do not readily diffuse across biological membranes.

However, in the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur.

For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case default value.

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in the absence of other data. By default, twice as high absorption is assumed compared to oral absorption (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

DERIVATION OF DNELs

DNELs derived from subchronic repeated dose toxicity NOAEL (OECD guideline 408)

 

Worker-DNEL long-term for inhalation route (systemic): 8.21 mg/m³

Start value: 113 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 98.58 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

                                             = 113 x 1/0.384 x 50/100 x 6.7/10

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 98.58 mg/m³ (8h-TWA)

Overall AF: 1*2*1*1*3*1*2 = 12

 

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.

 

Worker-DNEL long-term for dermal route (systemic):  2.35 mg/kg bw/d

Start value: 113 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 113 mg/kg bw/d

Overall AF: 1*2*4*1*3*1*2 = 48

 

DNELs derived from the fertility NOAEL to females (OECD guideline 421)

NOAELfertility females= 70 mg/kg bw/d (based on lower number of implantation sites)

An additional AF of 2 has been included taking account of remaining uncertainties due to read-across. No time extrapolation has to be applied because exposure time for females is comparable to OECD 415 (with the exception of post partum period)

Worker-DNEL long-term for inhalation route (systemic): 10.18 mg/m³

Start value: 70 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 61.07 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

                                             = 70 x 1/0.384 x 50/100 x 6.7/10

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 61.07 mg/m³ (8h-TWA)

Overall AF: 1*1*1*1*3*1*2 = 6

 

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.

 

Worker-DNEL long-term for dermal route (systemic):  2.92 mg/kg bw/d

Start value: 70 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 70 mg/kg bw/d

Overall AF: 1*1*4*1*3*1*2 = 24

 

 

DNELs derived from the fertility NOAEL to males (OECD guideline 421)

NOAELfertility males= 200 mg/kg bw/d (no specific findings on repro organs, spermatogenic staging profiles were normal for males examined = control and high dose males)

An additional AF of 2 has been included taking account of remaining uncertainties due to read-across. Time extrapolation 3 (sub-acute to sub-chronic according to REACH TGD R8)

In the OECD421-study no adverse effects were seen in males at 200 mg/kg bw/d concerning fertility, but in the preceding 14 day dose range finding study, all animals were sacrificed at 500 mg/kg bw/d. 

 

Worker-DNEL long-term for inhalation route (systemic): 9.69 mg/m³

Start value: 200 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 148.48 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

                                             = 200 x 1/0.384 x 50/100 x 6.7/10

The corrected inhalation NOAECworker (8h) is therefore:

                                             = 148.48 mg/m³ (8h-TWA)

Overall AF: 1*3*1*1*3*1*2 = 18

 

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.

 

Worker-DNEL long-term for dermal route (systemic): 2.78 mg/kg bw/d

Start value: 200 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 200 mg/kg bw/d

Overall AF: 1*3*4*1*3*1*2 = 72

 

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.45 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEC
Value:
49.05 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 inhalative.
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchonic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
default corrections for respiratory rate and respiratory volume have been included in route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known pathways for metabolism involving ubiquitous and non-specific enzyme systems (amidases/esterases, fatty acid metabolism) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
An additional AF of 2 has been included taking account of remaining uncertainties due to read-across.
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:
1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.41 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factos
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Value:
113 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 ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known pathways for metabolism involving ubiquitous and non-specific enzyme systems (amidases/esterases, fatty acid metabolism) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
An additional AF of 2 has been included taking account of remaining uncertainties due to read-across.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.41 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: informed assessment factors
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
Value:
113 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation required
AF for dose response relationship:
1
Justification:
Default ECHA AF for NOAEL used as starting point. The original NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
2
Justification:
Default assessment factor for extrapolation from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known pathways for metabolism involving ubiquitous and non-specific enzyme systems (amidases/esterases, fatty acid metabolism) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
2
Justification:
An additional AF of 2 has been included taking account of remaining uncertainties due to read-across.
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

Selection of the relevant dose descriptors:

Oral:

NOAEL =113 mg/kg bw/day: subchronic repeated dose toxicity study, rat, oral (gavage); read-across: Coco alkyl trimethyl ammonium chloride

 

NOAEL(development) = 200 mg/kg; NOAEL(male fertility) = 200 mg/kg bw/d; NOAEL(female fertility) = 70 mg/kg bw/d (reduced number of implantation sites at 200 mg/kg bw/d); read-across: Stearic acid 3-(dimethylaminopropyl)amide 

 

 

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

Oral absorption

The physicochemical properties of C16 Alkylamidopropyltrimethylammonium Chloride (log Kow = 2.49) and the molecular weight of 391.07 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion (molecular weight < 500 g/mol, log Kow between -1 and 4).

For chemical safety assessment an oral absorption rate of 100% is assumed as a worst case default value in the absence of other data

 

Dermal absorption

It is generally thought that ionised substances do not readily diffuse across biological membranes.

However, in the absence of detailed dermal penetration data it has to be assumed that dermal penetration may occur.

For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case default value.

 

Inhalation absorption

For chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in the absence of other data. By default, twice as high absorption is assumed compared to oral absorption (Guidance on Information Requirements and Chemical Safety Assessment, R8).

Extrapolation oral to inhalation: AF 2

 

DERIVATION OF DNELs

DNELs derived from subchronic repeated dose toxicity NOAEL (OECD guideline 408)

 

General population-DNEL long-term for inhalation route (systemic): 2.45 mg/m³

Start value: 113 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 49.05 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

                                             = 113 x 1/1.152 x 50/100

 

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

                                             = 49.05mg/m³ (24 h)

Overall AF: 1*2*1*1*5*1*2 = 20

 

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.

 

general population-DNEL long-term for dermal route (systemic):  1.41 mg/kg bw/d

Start value: 113 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 113 mg/kg bw/d

Overall AF: 1*2*4*1*5*1*2 = 80

 

general population-DNEL long-term for oral route (systemic):  1.41 mg/kg bw/d

Start value: 113 mg/kg bw/d

Route of original study: oral

Overall AF: 1*2*4*1*5*1*2 = 80

 

 

DNELs derived from the fertility NOAEL to females (OECD guideline 421)

NOAELfertility females= 70 mg/kg bw/d (based on lower number of implantation sites)

An additional AF of 2 has been included taking account of remaining uncertainties due to read-across. No time extrapolation has to be applied because exposure time for females is comparable to OECD 415 (with the exception of post partum period)

general population-DNEL long-term for inhalation route (systemic): 3.04 mg/m³

Start value: 70 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 30.38 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

                                             = 70 x 1/1.152 x 50/100

 

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

                                             = 30.38 mg/m³ (24 h)

Overall AF: 1*1*1*1*5*1*2 = 10

 

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.

 

general population-DNEL long-term for dermal route (systemic):  1.75 mg/kg bw/d

Start value: 70 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 70 mg/kg bw/d

Overall AF: 1*1*4*1*5*1*2 = 40

 

general population-DNEL long-term for oral route (systemic):  1.75 mg/kg bw/d

Start value: 70 mg/kg bw/d

Route of original study: oral

Overall AF: 1*1*4*1*5*1*2 = 40

 

 

DNELs derived from the fertility NOAEL to males (OECD guideline 421)

NOAELfertility males= 200 mg/kg bw/d (no specific findings on repro organs, spermatogenic staging profiles were normal for males examined = control and high dose males)

An additional AF of 2 has been included taking account of remaining uncertainties due to read-across. Time extrapolation 3 (sub-acute to sub-chronic according to REACH TGD R8)

In the OECD421-study no adverse effects were seen in males at 200 mg/kg bw/d concerning fertility, but in the preceding 14 day dose range finding study, all animals were sacrificed at 500 mg/kg bw/d. 

 

general population-DNEL long-term for inhalation route (systemic): 2.89 mg/m³

Start value: 200 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 86.81 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

                                             = 200 x 1/1.152 x 50/100

 

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

                                             = 86.81 mg/m³ (24 h)

Overall AF: 1*3*1*1*5*1*2 = 30

 

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.

 

general population-DNEL long-term for dermal route (systemic):  1.67 mg/kg bw/d

Start value: 200 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 200 mg/kg bw/d

Overall AF: 1*3*4*1*5*1*2 = 120

 

general population-DNEL long-term for oral route (systemic):  1.67 mg/kg bw/d

Start value: 200 mg/kg bw/d

Route of original study: oral

Overall AF: 1*3*4*1*5*1*2 = 120

 

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