Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: informed assessment factors

Overall assessment factor (AF):

36

Modified dose descriptor starting point:

NOAEC

Value:

61.07 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 reproductive/developmental screening 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:

6

Justification:

Default assessment factor for extrapolation from subacute 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 the lower sensitivity of the reproductive/developmental screening study concerning general toxicity compared to a repeated dose toxicity study.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.77 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

other: informed assessment factors

Overall assessment factor (AF):

72

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A dermal subchronic (90 d) repeated dose toxicity study is available, which showed no systemic toxicity. The more critical DNEL was derived from an oral reproduction/developmental toxicity screening 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:

3

Justification:

Time extrapolation: AF 3 (sub-acute to sub-chronic according to REACH TGD R8) for extrapolation from screening study to full reproduction toxicity study

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 the lower sensitivity of the screening study compared to a full reproduction toxicity study.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Deviation from REACH Assessment factors

Interspecies extrapolation; systemic effects

Based on the structure, the substance is likely to undergo hydrolysis by amidases, which in general have a broad substrate specificity and are present in rodents as well as in humans. Hydrolysis of C16-18 DMAPA amidoamine would result in mainly Stearic acid and Palmitic acid on the one hand and 3-Aminopropyldimethylamine on the other hand. The fatty acids are likely to enter the normal fatty acid metabolism and may be broken down to carbon dioxide or two carbon fragments, or be re-esterified to triacylglycerols and either metabolised for energy or stored in adipose tissue.

In general, lower primary aliphatic amines are metabolised to the corresponding carboxylic acid and urea. The tertiary site would be expected to undergo oxidation mediated bycytochrome P-450 or mixed function amine oxidases.

Based on this, no differences in the toxicodynamics are expected, and thus the use of the additional factor of 2.5 is not justified.

Intraspecies variability worker

Known pathways for degradation involving ubiquitous and non-specific enzyme systems (amidases/esterases,fatty acid metabolism) makes a lower variability likely, hence the AF of 3 as proposed by ECETOC (2010) is sufficiently conservative for workers.

Route-to-route extrapolation:

Oral absorption

The physicochemical properties of C16-18 DMAPA amidoamine are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion.

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

For chemical safety assessment a dermal absorption rate of 100% is assumed as a worst case default value based on the physicochemical properties and experimental data. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no AF (i.e. factor 1) should be introduced when performing oral-to-dermal extrapolation. (REACH TGD R8))

Inhalative absorption

For chemical safety assessment an inhalative absorption rate of 100% is assumed as a worst case default value in the absence of other data. By default an assessment factor of 2 for extrapolation oral to inhalation is introduced.

DNELs derived from reproduction/developmental NOAEL (OECD guideline 421); read across from Stearic acid 3-(dimethylaminopropyl)amide

The NOAEL for general toxicity was 70 mg/kg bw/d based on effects on body weight and food consumption at 200 mg/kg bw/d.

An additional AF of 2 has been included taking account of the lower sensitivity of the screening study compared to a repeated dose toxicity study (less parameters are examined).

For fertility, individual NOAELs for males and females have been identified.

In females, lower numbers of implantation sites (in the presence of maternal toxicity) have been noted in a reproduction/developmental screening study at 200 mg/kg bw/d. Thus, the NOAEL for female fertility in that study was 70 mg/kg bw/d.

Whereas no adverse effects for male fertility have been observed at 200 mg/kg bw/d in this study, but in the preceding 14 day dose range finding study all animals were sacrificed at 500 mg/kg bw/d (also showing absence of spermiation and degeneration of spermatids in the testes, oligospermia and seminiferous cell debris in the epididymides, and reduced contents in the prostate and seminal vesicles, which corresponded to a reduced size of seminal vesicles, prostate and epididymides at necropsy).

The NOAEL(fertility males) was 200 mg/kg bw/d (highest dose administered) based on no specific findings on reproductive organs and normal spermatogenic staging profiles for males examined (control and high dose males). An additional AF of 2 has been included taking account of the lower sensitivity of the screening study compared to a full reproduction toxicity study.

For male fertility an additional assessment factor for time extrapolation is required, as the exposure regime is different in the screening study (starting at 14 d prior to mating) and the definitive test (starting at 70 d prior to mating). As stated in the REACH TGD, time extrapolation from a subacute to subchronic study is required (AF 3). The extrapolation is from the screening test to the definitive test, which is not a chronic, but a subchronic study.

The NOAEL(fertility females) was 70 mg/kg bw/d based on lower number of implantation sites at 200 mg/kg bw/d. An additional AF of 2 has been included taking account of the lower sensitivity of the screening study compared to a full reproduction toxicity study.

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).

The NOAEL(development) was 200 mg/kg bw/d (highest dose administered) based on no developmental toxicity. An additional AF of 2 has been included taking account of the lower sensitivity of the screening study compared to a full developmental toxicity study.No time extrapolation factor has to be applied because the susceptible window is fully covered.

General parental toxicity

DNEL worker, chronic dermal systemic: 0.49 mg/kg bw/d

Start value: NOAEL(general toxicity)= 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: 4*6*3*1*1*2 = 144

DNEL worker, chronic inhalative systemic:1.70mg/m³

Start value: NOAEL(general toxicity) =70 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 61.07 mg/m³

inhalatory NOEC (8 h) = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

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

Overall AF: 1*6*3*1*1*2 = 36

Male fertility effects

DNEL worker, chronic dermal systemic: 2.77 mg/kg bw/d

Start value: NOAEL_{fertility males}200 mg/kg bw/d

Route of original study: oral exposure duration males 28 d

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

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

DNEL worker, chronic inhalative systemic: 9.69mg/m³

Start value: NOAEL_{fertility males}200 mg/kg bw/d

Route of original study: oral exposure duration males 28 d

Dose descriptor starting point after route-to-route extrapolation: 174.5 mg/m³

inhalatory NOEC (8 h) = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

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

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

Female fertility effects

DNEL worker, chronic dermal systemic: 2.92 mg/kg bw/d

Start value: NOAEL_{fertilityfemales}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: 4*1*3*1*1*2 = 24

DNEL worker, chronic inhalative systemic:10.18mg/m³

Start value: NOAEL_{fertilityfemales}70 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 61.07 mg/m³

inhalatory NOEC (8 h) = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

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

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

The DNELs for female fertility are higher than those for male fertility. Thus, the DNELs(fertility males) are also protective for female fertility.

Development

DNEL worker, chronic dermal systemic: 8.33 mg/kg bw/d

Start value: NOAEL_{developmental}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: 4*1*3*1*1*2 = 24

DNEL worker, chronic inhalative systemic:29.08mg/m³

Start value: NOAEL_{developmental}200 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 174.5 mg/m³

inhalatory NOEC (8 h) = oral NOAEL x 1/sRV_ratx ABS_oral-rat/ ABS_inh-humanx sRV_human/ wRV

= 20 x 1/0.384 x 50/100 x 6.7/10

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

The DNELs for developmental toxicity are higher than those for male fertility. Thus, the DNELs(fertility males) are also protective for development.

DNELs derived from repeated dose toxicity NOAEL (90-d study rabbit OECD guideline 411); read across from Stearic acid 3-(dimethylaminopropyl)amide

No signs of systemic toxicity were observed in this study, thus, the NOAEL was 200 mg/kg bw/d (highest dose administered). Dermal irritation was observed also at the lowest dose level of 5 mg/kg bw/d, which was the LOAEL for local effects. As no reliable dose descriptor could be derived from this study, low hazard for local effects after long term exposure should be assumed in analogy to the Guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation.

DNEL worker, chronic dermal systemic: 13.89 mg/kg bw/d

Start value: NOAEL 200 mg/kg bw/d

Route of original study: dermal, species rabbit

Overall AF: 2.4*1*3*2*1*1 = 14.4

The dermal repeated dose toxicity study should only be used for derivation of a dermal DNEL, thus no inhalative DNEL is calculated from this NOAEL. However, the dermal DNEL derived from this repeated dose toxicity study was higher than the dermal DNEL for male fertility. Thus, the DNEL(fertility males) is also protective for repeated dose toxicity.

DNELs derived from developmental NOAEL (OECD guideline 414, dermal, rabbit); read across from Stearic acid 3-(dimethylaminopropyl)amide

No signs of developmental toxicity have been observed at the highest administered dose of 200 mg/kg bw/d. Thus, the NOAEL_development= 200 mg/kg bw/d.

No time extrapolation factor has to be applied because the susceptible window is fully covered.

DNEL worker, chronic dermal systemic: 27.78 mg/kg bw/d

Start value: 200 mg/kg bw/d

Route of original study: dermal, rabbit

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

Overall AF: 2.4*1*3*1*1*1 = 7.2

The dermal developmental toxicity study should only be used for derivation of a dermal DNEL, thus no inhalative DNEL is calculated from this NOAEL. However, the dermal DNEL derived from this prenatal developmental toxicity study was higher than the dermal DNEL for male fertility. Thus, the DNEL(fertility males) is also protective for development.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.51 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: informed assessment factors

Overall assessment factor (AF):

60

Modified dose descriptor starting point:

NOAEC

Value:

30.38 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 reproductive/developmental screening 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:

6

Justification:

Default assessment factor for extrapolation from subacute 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 the lower sensitivity of the reproductive/developmental screening study concerning general toxicity compared to a repeated dose toxicity study.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 mg/kg bw/day

Most sensitive endpoint:

effect on fertility

Route of original study:

Oral

DNEL derivation method:

other: informed assessment factors

Overall assessment factor (AF):

120

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A dermal subchronic (90 d) repeated dose toxicity study is available, which showed no systemic toxicity. The more critical DNEL was derived from an oral reproduction/developmental toxicity screening 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:

3

Justification:

Time extrapolation: AF 3 (sub-acute to sub-chronic according to REACH TGD R8) for extrapolation from screening study to full reproduction toxicity study

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 the lower sensitivity of the screening study compared to a full reproduction toxicity study.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.29 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

other: informed assessment factors

Overall assessment factor (AF):

240

Modified dose descriptor starting point:

NOAEL

Value:

70 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not 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:

6

Justification:

Default assessment factor for extrapolation from subacute 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 the lower sensitivity of the reproductive/developmental screening study concerning general toxicity compared to a repeated dose toxicity study.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

medium hazard (no threshold derived)

Deviation from REACH Assessment factors

Interspecies extrapolation; systemic effects

Based on the structure, the substance is likely to undergo hydrolysis by amidases, which in general have a broad substrate specificity and are present in rodents as well as in humans. Hydrolysis of C16-18 DMAPA amidoamine would result in mainly Stearic acid and Palmitic acid on the one hand and 3-Aminopropyldimethylamine on the other hand. The fatty acids are likely to enter the normal fatty acid metabolism and may be broken down to carbon dioxide or two carbon fragments, or be re-esterified to triacylglycerols and either metabolised for energy or stored in adipose tissue.

In general, lower primary aliphatic amines are metabolised to the corresponding carboxylic acid and urea. The tertiary site would be expected to undergo oxidation mediated bycytochrome P-450 or mixed function amine oxidases.

Based on this, no differences in the toxicodynamics are expected, and thus the use of the additional factor of 2.5 is not justified.

Intraspecies variability general population

Known pathways for degradation involving ubiquitous and non-specific enzyme systems (amidases/esterases, fatty acid metabolism) makes a lower variability likely, hence the AF of 5 as proposed by ECETOC (2010) is sufficiently conservative for the general population.