Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.96 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:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

74 mg/m³

Explanation for the modification of the dose descriptor starting point:

results in lowest DNEL; for discussion, please see below

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:

1

Justification:

The substance is expected to be 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:

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)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 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:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

420 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

results in lowest DNEL; for discussion, please see below

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:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Route-to-route extrapolation:

Oral absorption

DIMAPDO has a molecular weight < 500 g/mol and a log Kow between -1 and 4 which is in general favourable for absorption. The estimated pka (Base) of 9.2 ± 0.4 means that the substance will be present almost completely ionised in the stomach (pH 2) and below 10% unionised in the small intestine (pH 8) 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. DIMAPDO has a very low water solubility below 0.1 mg/L and forms micelles in aqueous solutions (CMC = 0.009 g/L) which will additionally limit the absorption rate.

Therefore, an estimated absorption rate of 50 % may be appropriate for DIMAPDO.

Dermal absorption

Based on above data the substance may be absorbed dermally. The molecular weight < 500 g/mol, a log Kow between -1 and 4 favour a dermal absorption. Taking in account the pKa of 9.2 ± 0.4 meaning at skin pH of 5.5 almost all DIMAPDO molecules will be ionised and the very low water solubility < 0.1 mg/L a high dermal absorption is nevertheless unlikely. This is supported by a dermal absorption calculation using the IH SkinPerm model (v1.21). The absorbed fractions have been estimated to be 0% after 8 and 24 h and the absorbed amounts 0.12 and 0.35 mg after 8 and 24 h, respectively. The maximum dermal absorption rate has been calculated to be 3.60E-06 mg/cm²/h. Due to missing information about the applicability of the calculation model in respect to the substance under investigation the results should be treated with care.

Therefore, for exposure assessments a value of 10 % of absorption after dermal exposure may be appropriate.

Inhalation absorption

DIMAPDO is solid at room temperature and has a very high boiling point (> 300°C) together with a low vapour pressure (7.1E-009 Pa) therefore substance evaporation and uptake by inhalation as vapour is unlikely.

The uptake after direct inhalation of substance dust particles and aerosols is also very unlikely because DIMAPDO is marketed and used in a granular form (flakes) or as waxy liquid.

Nonetheless for chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in the absence of other data.

DNELs derived from the oral subacute study NOAEL (OECD guideline 408; source substance Coco amidopropyldimethylamine)

There were no mortalities or relevant clinical signs. Body weights, body weight gains and food consumption were unaffected. There were no adverse changes on ophthalmological, haematological or clinical chemistry parameters and no macroscopic changes or organ weight changes observed at gross necropsy. Histopathological examination revealed the presence of local proliferative lesions in the forestomach in all treatment groups, with an increasing incidence and severity. The lesions were characterized by areas of a thickened epithelial layer, frequently accompanied by hyperkeratosis and undulations at the basement membrane zone. Undulations are believed to be caused by the space occupying expansion of the epithelial layer of the forestomach and considered a secondary change. Signs of slight cellular atypia were noted in few males treated with 30 mg/kg/day bw/day and in a male and female treated with 60 mg/kg bw/day. The finding of obvious squamous cell hyperplasia (with early signs of atypia in some cases) in the non-glandular stomach of rats treated with 30 or 60 mg/kg bw/day is considered an adverse finding. Lesion in the non-glandular stomach of rodents however are considered clinically irrelevant since humans do not have a forestomach equivalent.

As no signs of systemic toxicity were observed, the NOAEL for systemic toxicity is 60 mg/kg bw, the highest dose tested in this study.

Hazard conclusions for workers based on the NOAEL of 60 mg/kg bw/d for general toxicity

Route

Type of effect

Hazard conclusion

Most sensitive endpoint

Inhalation

Systemic effects - Long-term

DNEL (Derived No Effect Level)

2.96mg/m³

repeated dose toxicity

(Oral)

Dermal

Systemic effects - Long-term

DNEL (Derived No Effect Level)

4.2mg/kg bw/day

repeated dose toxicity

(Oral)

Inhalation Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEC

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))

Dermal Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

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))

DNELs derived from reproduction/developmental NOAEL (OECD guideline 421; source substance 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.

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. 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(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). 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.

Hazard conclusions for workers based on the NOAEL of 70 mg/kg bw/d for female fertility effects

Route

Type of effect

Hazard conclusion

Most sensitive endpoint

Inhalation

Systemic effects - Long-term

DNEL (Derived No Effect Level)

5.92mg/m³

repeated dose toxicity

(Oral)

Dermal

Systemic effects - Long-term

DNEL (Derived No Effect Level)

8.4mg/kg bw/day

repeated dose toxicity

(Oral)

Inhalation Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEC

Default (DNEL calculator)

Overall Assessment Factor:12.5

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

AF for difference in duration of exposure:1 (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).)

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))

Dermal Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

Default (DNEL calculator)

Overall Assessment Factor:50

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

AF for difference in duration of exposure:1 (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).)

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))

Hazard conclusions for workers based on the NOAEL of 200 mg/kg bw/d for male fertility effects

Route

Type of effect

Hazard conclusion

Most sensitive endpoint

Inhalation

Systemic effects - Long-term

DNEL (Derived No Effect Level)

6.58mg/m³

effect on fertility

(Oral)

Dermal

Systemic effects - Long-term

DNEL (Derived No Effect Level)

9.33mg/kg bw/day

effect on fertility

(Oral)

Inhalation Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEC

Overall Assessment Factor:37.5

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

AF for difference in duration of exposure:3 (For male fertility an 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.)

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))

Dermal Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

Overall Assessment Factor:150

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

AF for difference in duration of exposure:3 (For male fertility an 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.)

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))

DNELs derived from reproduction/developmental NOAEL (OECD guideline 414; source substance Coco amidopropyldimethylamine)

Hazard conclusions for workers based on the NOAEL of 100 mg/kg bw/d

Route

Type of effect

Hazard conclusion

Most sensitive endpoint

Inhalation

Systemic effects - Long-term

DNEL (Derived No Effect Level)

9.87mg/m³

developmental toxicity / teratogenicity

(Oral)

Dermal

Systemic effects - Long-term

DNEL (Derived No Effect Level)

14mg/kg bw/day

developmental toxicity / teratogenicity

(Oral)

Inhalation Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEC

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, since the suceptible window is fully covered.)

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))

Dermal Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

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, since the suceptible window is fully covered.)

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))

Conclusion

The DNELs of the subchronic repeated-dose toxicity study (OECD 408) are also protective for male and female fertility and development.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.522 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:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

26.1 mg/m³

Explanation for the modification of the dose descriptor starting point:

results in lowest DNEL; for discussion, please see below

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:

medium hazard (no threshold derived)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 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:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

300 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

results in lowest DNEL; for discussion, please see below

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)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 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:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

results in lowest DNEL

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)

oute-to-route extrapolation:

Oral absorption

DIMAPDO has a molecular weight < 500 g/mol and a log Kow between -1 and 4 which is in general favourable for absorption. The estimated pka (Base) of 9.2 ± 0.4 means that the substance will be present almost completely ionised in the stomach (pH 2) and below 10% unionised in the small intestine (pH 8) 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. DIMAPDO has a very low water solubility below 0.1 mg/L and forms micelles in aqueous solutions (CMC = 0.009 g/L) which will additionally limit the absorption rate.

Therefore, an estimated absorption rate of 50 % may be appropriate for DIMAPDO.

Dermal absorption

Based on above data the substance may be absorbed dermally. The molecular weight < 500 g/mol, a log Kow between -1 and 4 favour a dermal absorption. Taking in account the pKa of 9.2 ± 0.4 meaning at skin pH of 5.5 almost all DIMAPDO molecules will be ionised and the very low water solubility < 0.1 mg/L a high dermal absorption is nevertheless unlikely. This is supported by a dermal absorption calculation using the IH SkinPerm model (v1.21). The absorbed fractions have been estimated to be 0% after 8 and 24 h and the absorbed amounts 0.12 and 0.35 mg after 8 and 24 h, respectively. The maximum dermal absorption rate has been calculated to be 3.60E-06 mg/cm²/h. Due to missing information about the applicability of the calculation model in respect to the substance under investigation the results should be treated with care.

Therefore, for exposure assessments a value of 10 % of absorption after dermal exposure may be appropriate.

Inhalation absorption

DIMAPDO is solid at room temperature and has a very high boiling point (> 300°C) together with a low vapour pressure (7.1E-009 Pa) therefore substance evaporation and uptake by inhalation as vapour is unlikely.

The uptake after direct inhalation of substance dust particles and aerosols is also very unlikely because DIMAPDO is marketed and used in a granular form (flakes) or as waxy liquid.

Nonetheless for chemical safety assessment an inhalation absorption rate of 100% is assumed as a worst case default value in the absence of other data.

DNELs derived from the oral subacute study NOAEL (OECD guideline 408; source substance Coco amidopropyldimethylamine)

There were no mortalities or relevant clinical signs. Body weights, body weight gains and food consumption were unaffected. There were no adverse changes on ophthalmological, haematological or clinical chemistry parameters and no macroscopic changes or organ weight changes observed at gross necropsy. Histopathological examination revealed the presence of local proliferative lesions in the forestomach in all treatment groups, with an increasing incidence and severity. The lesions were characterized by areas of a thickened epithelial layer, frequently accompanied by hyperkeratosis and undulations at the basement membrane zone. Undulations are believed to be caused by the space occupying expansion of the epithelial layer of the forestomach and considered a secondary change. Signs of slight cellular atypia were noted in few males treated with 30 mg/kg/day bw/day and in a male and female treated with 60 mg/kg bw/day. The finding of obvious squamous cell hyperplasia (with early signs of atypia in some cases) in the non-glandular stomach of rats treated with 30 or 60 mg/kg bw/day is considered an adverse finding. Lesion in the non-glandular stomach of rodents however are considered clinically irrelevant since humans do not have a forestomach equivalent.

As no signs of systemic toxicity were observed, the NOAEL for systemic toxicity is 60 mg/kg bw, the highest dose tested in this study.

Hazard conclusions for general population based on the NOAEL of 60 mg/kg bw/d for general toxicity

Route

Type of effect

Hazard conclusion

Most sensitive endpoint

Inhalation

Systemic effects - Long-term

DNEL (Derived No Effect Level)

0.522mg/m³

repeated dose toxicity

(Oral)

Dermal

Systemic effects - Long-term

DNEL (Derived No Effect Level)

1.5mg/kg bw/day

repeated dose toxicity

(Oral)

Oral

Systemic effects - Long-term

DNEL (Derived No Effect Level)

0.3mg/kg bw/day

repeated dose toxicity

(Oral)

Inhalation Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEC

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))

Dermal Systemic effects - Long-term

DNEL derivation method:

Dose descriptor starting point:NOAEL

Modified dose descriptor starting point:NOAEL

Overall Assessment Factor:200

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:10 (Default (DNEL calculator))

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

Oral Systemic effects - Long-term