Reaction mass of Amines, N-tallow alkyltrimethylenedi-, mono(2-ethylhexanoates), Amines, N-tallow alkyltrimethylenedi-, acetates and n-tallow-1,3-diaminopropane ditallate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.038 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.945 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting material for this reaction mass is n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4), that is reacted with tall oil fatty acids (CAS No 61790-12-3), 2-ethylhexanoic acid (CAS No 149-57-5) and acetic acid (CAS No 64-18-7). This reaction is carried out in mineral oil. The final product consists of ca. 77% mineral oil and ca. 23% of the reaction mixture. The presence of this high level of mineral oil makes it unsuitable for dosing to laboratory animals. While it was possible to synthesise small quantities of the pure reaction product without mineral oil for physiochemical and acute irritation testing, this was not possible for a repeat dose study where Kg quantities are required. There was therefore no other option other than to use read across to available data for main components in the reaction mixture, based on their toxicity profiles the n-tallow alkyltrimethyenediamine CAS No 1219010-04-4 is the critical component which will define the toxicity of the reaction mass as explained in the following paragraph.

The acetate and tallate (acetic acid and tall oil fatty acids) are not systemically toxic substances and would not be expected to contribute to any toxicity. The 2-ethylhexanoate however has a potential hazard as the 2-ethyl hexanoic acid (CAS No 149-57-5) is classified as category 2 for developmental toxicity. This substance has been reviewed in an extensive CoRAP process for REACH which included a new OECD422 and an EOGRTS OECD443 study with the additional DIT and DNT cohorts and a second generation. The top dose in this study was 800mg/kg based on the effects seen in the OECD442 study. In this study the NOAEL for the parental rats was 250mg/kg but the NOAEL for fertility and reproductive effects, developmental neurotoxicity and immunotoxicity effects was established at 800mg/kg bw/day due to a lack of effects. This indicates that the relatively minor adverse skeletal effects seen in the OECD 414 pre-natal development study in rats did not result in any observed adverse effects on the offspring in the new OECD443 study at a significantly higher dose level, the F1 rats successfully mating to produce a normal F2 generation.

The category 2 classification for developmental toxicity is therefore based on skeletal effects seen in rats in OECD414 pre-natal development studies. No such effects were seen in a rabbit OECD414 study. The effects seen in the rat OECD414 study were of skeletal variations in particular reduced ossification indicating embryo toxicity and increased incidence of club foot as an abnormality, with a NOAEL of 100mg/kg. It was shown the 2-ethylhexanoic acid affected the livers of the rats and resulted in changes in zinc metabolism that caused zinc deficiency in the embryos, which contributed to the effects seen but additional mechanisms could not be excluded.  The category 2 classification was confirmed during CoRAP. The studies indicated that the rats were specifically sensitive to such effects compared to rabbits based on this the relevance to humans is not clear.

The developmental toxicity of the 2-ethylhexanoic acid is a threshold effect with a clear NOAEL of 100mg/kg, the threshold nature of the effects seen only in the rat is supported in particular by the effect on zinc metabolism for which there was a clear threshold, no hazard to human health is anticipated at low exposures.

The n-tallow alkyltrimethyenediamine is ca. 52.2% of the reaction mixture with the 2-ethylhexanoic acid at 10.6% compared to the tall oil fatty acids at 32.2% and the acetic acid 4.6%. The NOAEL used for the diamine is 0.4mg/kg based on worst case read across to 90 day data for the C12-14 diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0).  Evaluation of the toxicity of the mixture based on diamine content only is appropriate as the other components do not significantly contribute and the DNELS will be sure to ensure that exposure to the 2-ethylhexanoate will be far below the DNEL calculated based on its 100mgkg NOAEL. It can be demonstrated that the level of 2- ethylhexanoate in the mixture is a factor 5 lower than the diamine, while its NOAEL is a factor 250 times higher. So relative contribution to toxicity is a factor 1000 lower than that for diamine, and consequently contribution by 2- ethylhexanoate can be ignored, just like that for acetate and tallate. Adjusting the NOAEL for the 52.2% of the diamine in the reaction mixture gives a point of departure for calculation of the DNELs of 0.76mg/kg. This will clearly adequately avoid any concern for effects from the 2-ethyl hexanoic acid component of the reaction mixture as it’s NOAEL of 100mg/kg if adjusted for the 10.6% in the reaction mixture would be 943.4 mg/kg.

n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4) is used as a starting point, cross-reading to the NOAEL 90-day on the C12-14-Diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0) of 0.4 mg/kgbw/d.   As the reaction mass being registered is 52.2% of the mixture and it is the ingredient responsible for the lead hazard the NOAEL has been adjusted to 0.766 mg/kg taking the percentage into account. ECHA guidance assumes 50% absorption orally and 100% absorption by inhalation, therefore the NOAEL is divide by 2 to give the point of departure. Allometric scaling is applied by taking account for the differentbreathing rates between rats and humans, as described in ECHA technical guidance the oral NOAEL in the rat mg/kg/day *1/0.38 * 6.7/10 = mg/m3 inhalation NOAEC for workers. An additional adjust was made as recommended in ECHA guidance R8.4.3. The oral exposure for the rats was 7 days a week but inhalation exposure of workers is considered to be 5 days a week. This is adjusted by dividing the NOEC by 5/7 or 0.714286.

AF for dose response relationship:

1

Justification:

No specific concerns; starting point is NOAEL, effects at LOAEL are not severe and probably of local nature.

AF for differences in duration of exposure:

2

Justification:

ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a
NOAEL from a 90 day study are derived using an assessment factor of 2 for extrapolation of the stu
dy duration to chronic exposure. As the NOAEL is from a 90 day study the factor of 2 was used.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already included in the route to route extrapolation from the rat oral NOAEL to the
equivalent human inhalation NOAEC.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.

AF for intraspecies differences:

5

Justification:

ECHA guidance recommends a factor of 5 for intraspecies differences for workers

AF for the quality of the whole database:

1

Justification:

While the DNEL is based on a read across substance is is considered to be a worst case due to the shorter carbon chain length C12-14 compared to the N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine.

AF for remaining uncertainties:

1

Justification:

The NOAEL of 0.4 mg/kgbw/d for C12-14-diamine is based on effects observed of foamy macrophages seen at higher dose levels of 1.5 and 6 mg/kg. The effects are comparable and evaluated similar as in all other studies involving primary amine structures, and are considered to be of a non-adverse and local nature. This NOAEL therefore represents a very conservative level.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.008 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The category 2 classification for developmental toxicity is therefore based on skeletal effects seen in rats in OECD414 pre-natal development studies. No such effects were seen in a rabbit OECD414 study. The effects seen in the rat OECD414 study were of skeletal variations in particular reduced ossification indicating embryo toxicity and increased incidence of club foot as an abnormality, with a NOAEL of 100mg/kg. It was shown the 2-ethylhexanoic acid affected the livers of the rats and resulted in changes in zinc metabolism that caused zinc deficiency in the embryos, which contributed to the effects seen but additional mechanisms could not be excluded.  The category 2 classification was confirmed during CoRAP. The studies indicated that the rats were specifically sensitive to such effects compared to rabbits based on this the relevance to humans is not clear.

The developmental toxicity of the 2-ethylhexanoic acid is a threshold effect with a clear NOAEL of 100mg/kg, the threshold nature of the effects seen only in the rat is supported in particular by the effect on zinc metabolism for which there was a clear threshold, no hazard to human health is anticipated at low exposures.

 

The n-tallow alkyltrimethyenediamine is ca. 52.2% of the reaction mixture with the 2-ethylhexanoic acid at 10.6% compared to the tall oil fatty acids at 32.2% and the acetic acid 4.6%. The NOAEL used for the diamine is 0.4mg/kg based on worst case read across to 90 day data for the C12-14 diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0).  Evaluation of the toxicity of the mixture based on diamine content only is appropriate as the other components do not significantly contribute and the DNELS will be sure to ensure that exposure to the 2-ethylhexanoate will be far below the DNEL calculated based on its 100mgkg NOAEL. It can be demonstrated that the level of 2- ethylhexanoate in the mixture is a factor 5 lower than the diamine, while its NOAEL is a factor 250 times higher. So relative contribution to toxicity is a factor 1000 lower than that for diamine, and consequently contribution by 2- ethylhexanoate can be ignored, just like that for acetate and tallate. Adjusting the NOAEL for the 52.2% of the diamine in the reaction mixture gives a point of departure for calculation of the DNELs of 0.76mg/kg. This will clearly adequately avoid any concern for effects from the 2-ethyl hexanoic acid component of the reaction mixture as it’s NOAEL of 100mg/kg if adjusted for the 10.6% in the reaction mixture would be 943.4 mg/kg.

 

n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4) is used as a starting point, cross-reading to the NOAEL 90-day on the C12-14-Diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0) of 0.4 mg/kgbw/d.   As the reaction mass being registered is 52.2% of the mixture and it is the ingredient responsible for the lead hazard the NOAEL has been adjusted to 0.766 mg/kg taking the percentage into account.

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

2

Justification:

ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study are derived using an assessment factor of 2 for extrapolation of the stu
dy duration to chronic exposure. As the NOAEL is from a 90 day study the factor of 2 was used.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA guidance recommends as factor of 4 for Allometric scaling from effects in the rat to humans, to compensate for the different metabolic rates.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.

AF for intraspecies differences:

5

Justification:

ECHA guidance recommends a factor of 5 for intraspecies differences for workers.

AF for the quality of the whole database:

1

Justification:

While the DNEL is based on a read across substance is is considered to be a wosrts case due to the shorter carbon chain length C12-14 compared to the N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine.

AF for remaining uncertainties:

1

Justification:

The NOAEL of 0.4 mg/kgbw/d for C12-14-diamine is based on effects observed of foamy macrophages seen at higher dose levels of 1.5 and 6 mg/kg. The effects are comparable and evaluated similar as in all other studies involving primary amine structures, and are considered to be of a non-adverse and local nature. This NOAEL therefore represents a very conservative level.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.006 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

0.284 mg/m³

Explanation for the modification of the dose descriptor starting point:

The starting material for this reaction mass is n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4), that is reacted with tall oil fatty acids (CAS No 61790-12-3), 2-ethylhexanoic acid (CAS No 149-57-5) and acetic acid (CAS No 64-18-7). This reaction is carried out in mineral oil. The final product consists of ca. 77% mineral oil and ca. 23% of the reaction mixture. The presence of this high level of mineral oil makes it unsuitable for dosing to laboratory animals. While it was possible to synthesise small quantities of the pure reaction product without mineral oil for physiochemical and acute irritation testing, this was not possible for a repeat dose study where Kg quantities are required. There was therefore no other option other than to use read across to available data for main components in the reaction mixture, based on their toxicity profiles the n-tallow alkyltrimethyenediamine CAS No 1219010-04-4 is the critical component which will define the toxicity of the reaction mass as explained in the following paragraph.

 

The acetate and tallate (acetic acid and tall oil fatty acids) are not systemically toxic substances and would not be expected to contribute to any toxicity. The 2-ethylhexanoate however has a potential hazard as the 2-ethyl hexanoic acid (CAS No 149-57-5) is classified as category 2 for developmental toxicity. This substance has been reviewed in an extensive CoRAP process for REACH which included a new OECD422 and an EOGRTS OECD443 study with the additional DIT and DNT cohorts and a second generation. The top dose in this study was 800mg/kg based on the effects seen in the OECD442 study. In this study the NOAEL for the parental rats was 250mg/kg but the NOAEL for fertility and reproductive effects, developmental neurotoxicity and immunotoxicity effects was established at 800mg/kg bw/day due to a lack of effects. This indicates that the relatively minor adverse skeletal effects seen in the OECD 414 pre-natal development study in rats did not result in any observed adverse effects on the offspring in the new OECD443 study at a significantly higher dose level, the F1 rats successfully mating to produce a normal F2 generation.

 

The category 2 classification for developmental toxicity is therefore based on skeletal effects seen in rats in OECD414 pre-natal development studies. No such effects were seen in a rabbit OECD414 study. The effects seen in the rat OECD414 study were of skeletal variations in particular reduced ossification indicating embryo toxicity and increased incidence of club foot as an abnormality, with a NOAEL of 100mg/kg. It was shown the 2-ethylhexanoic acid affected the livers of the rats and resulted in changes in zinc metabolism that caused zinc deficiency in the embryos, which contributed to the effects seen but additional mechanisms could not be excluded.  The category 2 classification was confirmed during CoRAP. The studies indicated that the rats were specifically sensitive to such effects compared to rabbits based on this the relevance to humans is not clear.

The developmental toxicity of the 2-ethylhexanoic acid is a threshold effect with a clear NOAEL of 100mg/kg, the threshold nature of the effects seen only in the rat is supported in particular by the effect on zinc metabolism for which there was a clear threshold, no hazard to human health is anticipated at low exposures.

 

The n-tallow alkyltrimethyenediamine is ca. 52.2% of the reaction mixture with the 2-ethylhexanoic acid at 10.6% compared to the tall oil fatty acids at 32.2% and the acetic acid 4.6%. The NOAEL used for the diamine is 0.4mg/kg based on worst case read across to 90 day data for the C12-14 diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0).  Evaluation of the toxicity of the mixture based on diamine content only is appropriate as the other components do not significantly contribute and the DNELS will be sure to ensure that exposure to the 2-ethylhexanoate will be far below the DNEL calculated based on its 100mgkg NOAEL. It can be demonstrated that the level of 2- ethylhexanoate in the mixture is a factor 5 lower than the diamine, while its NOAEL is a factor 250 times higher. So relative contribution to toxicity is a factor 1000 lower than that for diamine, and consequently contribution by 2- ethylhexanoate can be ignored, just like that for acetate and tallate. Adjusting the NOAEL for the 52.2% of the diamine in the reaction mixture gives a point of departure for calculation of the DNELs of 0.76mg/kg. This will clearly adequately avoid any concern for effects from the 2-ethyl hexanoic acid component of the reaction mixture as it’s NOAEL of 100mg/kg if adjusted for the 10.6% in the reaction mixture would be 943.4 mg/kg.

 

n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4) is used as a starting point, cross-reading to the NOAEL 90-day on the C12-14-Diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0) of 0.4 mg/kgbw/d.   As the reaction mass being registered is 52.2% of the mixture and it is the ingredient responsible for the lead hazard the NOAEL has been adjusted to 0.766 mg/kg taking the percentage into account. ECHA guidance assumes 50% absorption orally and 100% absorption by inhalation, therefore the NOAEL is divided by 2 to give the point of departure.

Allometric scaling is applied by taking account for the different breathing rates between rats and humans, as described in IUCLID Calculator the oral NOAEL in the rat mg/kg/

day *1/1.35 mg/m3 inhalation NOAEC for the general population (based on 60 kg bodyweight rather than 70 kg for workers).

AF for dose response relationship:

1

Justification:

No specific concerns; starting point is NOAEL, effects at LOAEL are not severe and probably of local nature.

AF for differences in duration of exposure:

2

Justification:

ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study are derived using an assessment factor of 2 for extrapolation of the stu
dy duration to chronic exposure. As the NOAEL is from a 90 day study the factor of 2 was used.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already included in the route to route extrapolation from the rat oral NOAEL to the equivalent human inhalation NOAEC.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.

AF for intraspecies differences:

10

Justification:

ECHA guidance recommends a factor of 10 for intraspecies differences for the general population.

AF for the quality of the whole database:

1

Justification:

While the DNEL is based on a read across substance is is considered to be a worst case due to the shorter carbon chain length C12-14 compared to the N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine.

AF for remaining uncertainties:

1

Justification:

The NOAEL of 0.4 mg/kgbw/d for C12-14-diamine is based on effects observed of foamy macrophages seen at higher dose levels of 1.5 and 6 mg/kg. The effects are comparable and evaluated similar as in all other studies involving primary amine structures, and are considered to be of a non-adverse and local nature. This NOAEL therefore represents a very conservative level.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.004 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting material for this reaction mass is n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4), that is reacted with tall oil fatty acids (CAS No 61790-12-3), 2-ethylhexanoic acid (CAS No 149-57-5) and acetic acid (CAS No 64-18-7). This reaction is carried out in mineral oil. The final product consists of ca. 77% mineral oil and ca. 23% of the reaction mixture. The presence of this high level of mineral oil makes it unsuitable for dosing to laboratory animals. While it was possible to synthesise small quantities of the pure reaction product without mineral oil for physiochemical and acute irritation testing, this was not possible for a repeat dose study where Kg quantities are required. There was therefore no other option other than to use read across to available data for main components in the reaction mixture, based on their toxicity profiles the n-tallow alkyltrimethyenediamine CAS No 1219010-04-4 is the critical component which will define the toxicity of the reaction mass as explained in the following paragraph.

 

The acetate and tallate (acetic acid and tall oil fatty acids) are not systemically toxic substances and would not be expected to contribute to any toxicity. The 2-ethylhexanoate however has a potential hazard as the 2-ethyl hexanoic acid (CAS No 149-57-5) is classified as category 2 for developmental toxicity. This substance has been reviewed in an extensive CoRAP process for REACH which included a new OECD422 and an EOGRTS OECD443 study with the additional DIT and DNT cohorts and a second generation. The top dose in this study was 800mg/kg based on the effects seen in the OECD442 study. In this study the NOAEL for the parental rats was 250mg/kg but the NOAEL for fertility and reproductive effects, developmental neurotoxicity and immunotoxicity effects was established at 800mg/kg bw/day due to a lack of effects. This indicates that the relatively minor adverse skeletal effects seen in the OECD 414 pre-natal development study in rats did not result in any observed adverse effects on the offspring in the new OECD443 study at a significantly higher dose level, the F1 rats successfully mating to produce a normal F2 generation.

 

The category 2 classification for developmental toxicity is therefore based on skeletal effects seen in rats in OECD414 pre-natal development studies. No such effects were seen in a rabbit OECD414 study. The effects seen in the rat OECD414 study were of skeletal variations in particular reduced ossification indicating embryo toxicity and increased incidence of club foot as an abnormality, with a NOAEL of 100mg/kg. It was shown the 2-ethylhexanoic acid affected the livers of the rats and resulted in changes in zinc metabolism that caused zinc deficiency in the embryos, which contributed to the effects seen but additional mechanisms could not be excluded.  The category 2 classification was confirmed during CoRAP. The studies indicated that the rats were specifically sensitive to such effects compared to rabbits based on this the relevance to humans is not clear.

The developmental toxicity of the 2-ethylhexanoic acid is a threshold effect with a clear NOAEL of 100mg/kg, the threshold nature of the effects seen only in the rat is supported in particular by the effect on zinc metabolism for which there was a clear threshold, no hazard to human health is anticipated at low exposures.

 

The n-tallow alkyltrimethyenediamine is ca. 52.2% of the reaction mixture with the 2-ethylhexanoic acid at 10.6% compared to the tall oil fatty acids at 32.2% and the acetic acid 4.6%. The NOAEL used for the diamine is 0.4mg/kg based on worst case read across to 90 day data for the C12-14 diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0).  Evaluation of the toxicity of the mixture based on diamine content only is appropriate as the other components do not significantly contribute and the DNELS will be sure to ensure that exposure to the 2-ethylhexanoate will be far below the DNEL calculated based on its 100mgkg NOAEL. It can be demonstrated that the level of 2- ethylhexanoate in the mixture is a factor 5 lower than the diamine, while its NOAEL is a factor 250 times higher. So relative contribution to toxicity is a factor 1000 lower than that for diamine, and consequently contribution by 2- ethylhexanoate can be ignored, just like that for acetate and tallate. Adjusting the NOAEL for the 52.2% of the diamine in the reaction mixture gives a point of departure for calculation of the DNELs of 0.76mg/kg. This will clearly adequately avoid any concern for effects from the 2-ethyl hexanoic acid component of the reaction mixture as it’s NOAEL of 100mg/kg if adjusted for the 10.6% in the reaction mixture would be 943.4 mg/kg.

 

n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4) is used as a starting point, cross-reading to the NOAEL 90-day on the C12-14-Diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0) of 0.4 mg/kgbw/d.   As the reaction mass being registered is 52.2% of the mixture and it is the ingredient responsible for the lead hazard the NOAEL has been adjusted to 0.766 mg/kg taking the percentage into account. 

Diamines are not expected to easily pass the skin in view of its ionised form at physiological conditions. However, as this is not quantitatively evaluated, 100% dermal absorption is considered as worst case assumption.

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

2

Justification:

ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study are derived using an assessment factor of 2 for extrapolation of the study duration to chronic exposure. As the NOAEL is from a 90 day study the factor of 2 was used.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA guidance recommends as factor of 4 for Allometric scaling from effects in the rat to humans, to compensate for the different metabolic rates.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.

AF for intraspecies differences:

10

Justification:

ECHA guidance recommends a factor of 10 for intraspecies differences for the general population

AF for the quality of the whole database:

1

Justification:

While the DNEL is based on a read across substance is is considered to be a worst case due to the shorter carbon chain length C12-14 compared to the N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine.

AF for remaining uncertainties:

1

Justification:

The NOAEL of 0.4 mg/kgbw/d for C12-14-diamine is based on effects observed of foamy macrophages seen at higher dose levels of 1.5 and 6 mg/kg. The effects are comparable and evaluated similar as in all other studies involving primary amine structures, and are considered to be of a non-adverse and local nature. This NOAEL therefore represents a very conservative level.

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:

0.004 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

0.766 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The starting material for this reaction mass is n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4), that is reacted with tall oil fatty acids (CAS No 61790-12-3), 2-ethylhexanoic acid (CAS No 149-57-5) and acetic acid (CAS No 64-18-7). This reaction is carried out in mineral oil. The final product consists of ca. 77% mineral oil and ca. 23% of the reaction mixture. The presence of this high level of mineral oil makes it unsuitable for dosing to laboratory animals. While it was possible to synthesise small quantities of the pure reaction product without mineral oil for physiochemical and acute irritation testing, this was not possible for a repeat dose study where Kg quantities are required. There was therefore no other option other than to use read across to available data for main components in the reaction mixture, based on their toxicity profiles the n-tallow alkyltrimethyenediamine CAS No 1219010-04-4 is the critical component which will define the toxicity of the reaction mass as explained in the following paragraph.

 

The acetate and tallate (acetic acid and tall oil fatty acids) are not systemically toxic substances and would not be expected to contribute to any toxicity. The 2-ethylhexanoate however has a potential hazard as the 2-ethyl hexanoic acid (CAS No 149-57-5) is classified as category 2 for developmental toxicity. This substance has been reviewed in an extensive CoRAP process for REACH which included a new OECD422 and an EOGRTS OECD443 study with the additional DIT and DNT cohorts and a second generation. The top dose in this study was 800mg/kg based on the effects seen in the OECD442 study. In this study the NOAEL for the parental rats was 250mg/kg but the NOAEL for fertility and reproductive effects, developmental neurotoxicity and immunotoxicity effects was established at 800mg/kg bw/day due to a lack of effects. This indicates that the relatively minor adverse skeletal effects seen in the OECD 414 pre-natal development study in rats did not result in any observed adverse effects on the offspring in the new OECD443 study at a significantly higher dose level, the F1 rats successfully mating to produce a normal F2 generation.

 

The category 2 classification for developmental toxicity is therefore based on skeletal effects seen in rats in OECD414 pre-natal development studies. No such effects were seen in a rabbit OECD414 study. The effects seen in the rat OECD414 study were of skeletal variations in particular reduced ossification indicating embryo toxicity and increased incidence of club foot as an abnormality, with a NOAEL of 100mg/kg. It was shown the 2-ethylhexanoic acid affected the livers of the rats and resulted in changes in zinc metabolism that caused zinc deficiency in the embryos, which contributed to the effects seen but additional mechanisms could not be excluded.  The category 2 classification was confirmed during CoRAP. The studies indicated that the rats were specifically sensitive to such effects compared to rabbits based on this the relevance to humans is not clear.

The developmental toxicity of the 2-ethylhexanoic acid is a threshold effect with a clear NOAEL of 100mg/kg, the threshold nature of the effects seen only in the rat is supported in particular by the effect on zinc metabolism for which there was a clear threshold, no hazard to human health is anticipated at low exposures.

 

The n-tallow alkyltrimethyenediamine is ca. 52.2% of the reaction mixture with the 2-ethylhexanoic acid at 10.6% compared to the tall oil fatty acids at 32.2% and the acetic acid 4.6%. The NOAEL used for the diamine is 0.4mg/kg based on worst case read across to 90 day data for the C12-14 diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0).  Evaluation of the toxicity of the mixture based on diamine content only is appropriate as the other components do not significantly contribute and the DNELS will be sure to ensure that exposure to the 2-ethylhexanoate will be far below the DNEL calculated based on its 100mgkg NOAEL. It can be demonstrated that the level of 2- ethylhexanoate in the mixture is a factor 5 lower than the diamine, while its NOAEL is a factor 250 times higher. So relative contribution to toxicity is a factor 1000 lower than that for diamine, and consequently contribution by 2- ethylhexanoate can be ignored, just like that for acetate and tallate. Adjusting the NOAEL for the 52.2% of the diamine in the reaction mixture gives a point of departure for calculation of the DNELs of 0.76mg/kg. This will clearly adequately avoid any concern for effects from the 2-ethyl hexanoic acid component of the reaction mixture as it’s NOAEL of 100mg/kg if adjusted for the 10.6% in the reaction mixture would be 943.4 mg/kg.

 

n-tallow alkyltrimethyenediamine CAS No 61791-55-7, which was registered for REACH as N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine(CAS No 1219010-04-4) is used as a starting point, cross-reading to the NOAEL 90-day on the C12-14-Diamine (Amines, N-C12-14-alkyltriemtylendi CAS No 90640-43-0) of 0.4 mg/kgbw/d.   As the reaction mass being registered is 52.2% of the mixture and it is the ingredient responsible for the lead hazard the NOAEL has been adjusted to 0.766 mg/kg taking the percentage into account. No adjustment is required when using this as the basis for calculating an oral DNEL for the general population.

AF for dose response relationship:

1

Justification:

No specific concerns. Effects at LOAEL are not severe and probably only of local nature.

AF for differences in duration of exposure:

2

Justification:

ECHA guidance document Chapter R8, in Appendix R.8-12, indicates that DNELS derived using a NOAEL from a 90 day study are derived using an assessment factor of 2 for extrapolation of the study duration to chronic exposure. As the NOAEL is from a 90 day study the factor of 2 was used.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA guidance recommends as factor of 4 for Allometric scaling from effects in the rat to humans, to compensate for the different metabolic rates.

AF for other interspecies differences:

2.5

Justification:

ECHA guidance recommends an additional factor of 2.5 for other interspecies differences, therefore a factor of 2.5 has been applied.

AF for intraspecies differences:

10

Justification:

ECHA guidance recommends a factor of 10 for intraspecies differences for the general population.

AF for the quality of the whole database:

1

Justification:

While the DNEL is based on a read across substance is is considered to be a worst case due to the shorter carbon chain length C12-14 compared to the N-C16-18-alkyl(evennumbered) C18 unsaturated propane-1, 3-diamine.

AF for remaining uncertainties:

1

Justification:

The NOAEL of 0.4 mg/kgbw/d for C12-14-diamine is based on effects observed of foamy macrophages seen at higher dose levels of 1.5 and 6 mg/kg. The effects are comparable and evaluated similar as in all other studies involving primary amine structures, and are considered to be of a non-adverse and local nature. This NOAEL therefore represents a very conservative level.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

No exposure of the general population to the reaction mass based on the uses indicated in this dossier that are limited to industrial manufacture and formulation and professional uses. However, to allow for evaluation from indirect exposures via the environment, DNELs have been derived for systemic toxicity from long term exposures via all routes.