Aspartic acid, N,N'-(2-methyl-1,5-pentanediyl)bis-, 1,1',4,4'-tetraethyl ester

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

50 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):

7

Modified dose descriptor starting point:

NOAEC

Value:

353 mg/m³

Explanation for the modification of the dose descriptor starting point:

A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2012) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also, anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the substance is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed and that the acute studies that were performed with oral and inhalation route of exposure did not give evidence for a route specific systemic toxicity.

AF for dose response relationship:

1

AF for differences in duration of exposure:

1.4

Justification:

For extrapolation of exposure duration subchronic to chronic: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4.

AF for interspecies differences (allometric scaling):

1

Justification:

Already covered by correction of starting point. Correction was according to Figure R.8 in the Guidance Document R.8 (ECHA, 2012): Corrected inhalatory NOAEC = oral NOAEL * 1/0.38 kg/m³ * 6.7 m³/10 m³.

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral or aerosol inhalation study. In a subacute (OECD 407) and a subchronic (OECD 408) study mild kidney effects (cortical tubular vacuolation) were seen at 1000 mg/kg. These findings were considered to be due to a storage process, and were shown to be be reversible in a two-weeks post exposure recovery in the subacute study. The DNEL derivation based on a NOAEL of 200 mg/kg bw/day with only mild effects at the next higher dose of 1000 mg/kg bw/day is already very conservative, therefore no correction for remaining interspecies differences has to be done, resulting in a factor 1.

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

Justification:

The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

200 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7 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):

28

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Absorption oral compared to dermal assumed to be identical

AF for dose response relationship:

1

AF for differences in duration of exposure:

1.4

Justification:

For extrapolation of exposure duration subchronic to chronic: The suggested factor 2 for extrapolation of exposure duration subchronic (90 days) to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4.

AF for interspecies differences (allometric scaling):

4

Justification:

Differences rat vs. human

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral or aerosol inhalation study. In a subacute (OECD 407) and a subchronic (OECD 408) study mild kidney effects (cortical tubular vacuolation) were seen at 1000 mg/kg. These findings were considered to be due to a storage process, and were shown to be be reversible in a two-weeks post exposure recovery in the subacute study. The DNEL derivation based on a NOAEL of 200 mg/kg bw/day with only mild effects at the next higher dose of 1000 mg/kg bw/day is already very conservative, therefore no correction for remaining interspecies differences has to be done, resulting in a factor 1.

AF for intraspecies differences:

5

AF for the quality of the whole database:

1

Justification:

The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

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:

no hazard identified

Additional information - workers

The available studies show that the acute toxicity of aspartic acid, N,N'-(2-methyl-1,5-pentanediyl)bis-, 1,1',4,4'-tetraethyl ester is low (LD50 > 2000 mg/kg bw; LC50 > 4923 mg/m³). It is noteworthy that there does not appear to be any route-dependent systemic toxicity by reviewing the results of the acute oral (Stropp, 1999a) and inhalation (Pauluhn, 1999) studies for this substance.

Slight dermal (Leuschner, 1999a) and respiratory tract (Pauluhn, 1999) irritation were observed in the acute studies but are not considered sufficient to influence the determination of a DNEL. No dermal sensitisation potential was found (Stropp, 1999b).

Generally, repeated exposure studies are considered to be more reliable for defining the toxicity profile of chemicals and extrapolating the results to human exposure regimens. Because of the absence of any differentiating route-dependent systemic toxicity revealed by the acute studies, the low irritation potential, and their greater relevance in predicting human toxicity to chemicals, the subchronic oral toxicity study (Schladt, 2012) was chosen as key study for defining both the DNELs for inhalation and for dermal exposure. Thus, the NOAEL of 200 mg/kg bw/day was considered to be the point of departure.

 

The DNEL_{long-term, systemic} for workers for oral/dermal exposure and for inhalative exposure is derived as follows: 

DNEL_{long-term, systemic for oral/dermal exposure} for workers using default extrapolation factors¹:

Oral NOAEL (rat) from a subacute toxicity study:                                200 mg/kg bw/day

Absorption oral compared to dermal assumed to be identical:              1

For interspecies differences rat vs. human (allometric scaling):               4

²For remaining interspecies differences:                                                1

For intraspecies differences in workers:                                                5

³For extrapolation of exposure duration subchronic to chronic:             1.4

For reliability of dose-response:                                                           1

For quality of whole database:                                                             1

Overall factor:                                                                                   28

Worker DNEL_{long-term, systemic for oral/dermal exposure}:      7 mg/kg bw/day

 

DNEL_{long-term, systemic for inhalative exposure} for workers using default extrapolation factors¹:

Oral NOAEL (rat) from a subacute toxicity study:                                200 mg/kg bw/day

Correction of the starting point according to Figure R.8 -3 in the Guidance Document R.8 (ECHA, 2012):

Corrected inhalatory NOAEL = oral NOAEL * 1/0.38 m³/kg * 6.7m³/10m³

Corrected inhalatory NOAEL for workers =                              353 mg/m³

⁴Absorption oral compared to inhalative:                                             1

For interspecies differences rat vs. human (allometric scaling):              1 (already covered by correction of starting point)

²For remaining interspecies differences:                                               1

For intraspecies differences in workers:                                               5

³For extrapolation of exposure duration subacute to chronic:               1.4

For reliability of dose-response:                                                          1

For quality of whole database:                                                            1

Overall factor:                                                                                    7

Worker DNEL_{long-term, systemic for inhalative exposure}:  50 mg/m³

¹: default factors according to Guidance Document R.8 (ECHA, 2012)

²: A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral and an aerosol inhalation study. The DNEL derivation based on a NOAEL of 200 mg/kg bw/day with only mild effects at the next higher dose of 1000 mg/kg bw/day (limit dose) is already very conservative, therefore no correction for remaining interspecies differences has to be done, resulting in a factor 1.

³: The suggested factor 6 for extrapolation of exposure duration subchronic to chronic was corrected for difference in number of days of exposure per week (7 days/week in animal study versus 5 days/week for workers). Thus, the total AF is 2 * 0.7 = 1.4.

⁴: A factor 2 is suggested bythe Guidance Document R.8 (ECHA, 2012) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also, anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., Toxicol. Appl. Pharmacol. 152, 211 -231, 1998; Harkema, Toxicol. Pathol. 19, 4, 321 -336, 1991). Therefore a factor 1 is chosen for route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the substance is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed (Pauluhn, 1999) and that the acute studies that were performed with oral and inhalation route of exposure did not give evidence for a route specific systemic toxicity.

 

Due to the slight respiratory irritation potential of the substance shown in an acute inhalation study there is no need to derive an acute DNEL for local toxicity. It is proposed to limit exposure peaks to a factor of 4. This approach is in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900, published by the German Federal Ministry of Labour and Social Affairs) and also with ECHA Guidance (2012), Chapter R.8., Appendix R.8 -8, box 6.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 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):

20

Modified dose descriptor starting point:

NOAEC

Value:

174 mg/m³

Explanation for the modification of the dose descriptor starting point:

A factor 2 is suggested by the Guidance Document R.8 (ECHA, 2012) for the oral-to-inhalation extrapolation, but justified deviations are possible. Concerning inhalation, rats are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Also, anatomical differences as well as air flow patterns between rodents and humans are to be taken into account (e.g. in case of effects at the olfactory epithelium; see Frederick et. al., 1998, Harkema, 1991). Therefore a factor 1 is chosen for route extrapolation. This provides sufficient protection, taking additionally into account that the respiratory tract’s toxicity of the substance is characterised by a low potential for upper respiratory tract irritation and no systemic toxicity at all could be observed and that the acute studies that were performed with oral and inhalation route of exposure did not give evidence for a route specific systemic toxicity.

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

For extrapolation of exposure duration subchronic to chronic.

AF for interspecies differences (allometric scaling):

1

Justification:

Already covered by correction of starting point. Correction was according to Figure R.8 in the Guidance Document R.8 (ECHA, 2012): Corrected inhalatory LOAEC = oral LOAEL * 1/1.15 m³/kg.

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral or aerosol inhalation study. In a subacute (OECD 407) and a subchronic (OECD 408) study mild kidney effects (cortical tubular vacuolation) were seen at 1000 mg/kg. These findings were considered to be due to a storage process, and were shown to be be reversible in a two-weeks post exposure recovery in the subacute study. The DNEL derivation based on a NOAEL of 200 mg/kg bw/day with only mild effects at the next higher dose of 1000 mg/kg bw/day is already very conservative, therefore no correction for remaining interspecies differences has to be done, resulting in a factor 1.

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

Justification:

The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

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:

2.5 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):

80

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Absorption oral compared to dermal assumed to be identical

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

For extrapolation of exposure duration subchronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Differences rat vs. human

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral or aerosol inhalation study. In a subacute (OECD 407) and a subchronic (OECD 408) study mild kidney effects (cortical tubular vacuolation) were seen at 1000 mg/kg. These findings were considered to be due to a storage process, and were shown to be be reversible in a two-weeks post exposure recovery in the subacute study. The DNEL derivation based on a NOAEL of 200 mg/kg bw/day with only mild effects at the next higher dose of 1000 mg/kg bw/day is already very conservative, therefore no correction for remaining interspecies differences has to be done, resulting in a factor 1.

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

Justification:

The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

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:

2.5 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):

80

Modified dose descriptor starting point:

NOAEL

Value:

200 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

For extrapolation of exposure duration subchronic to chronic.

AF for interspecies differences (allometric scaling):

4

Justification:

Differences rat vs. human

AF for other interspecies differences:

1

Justification:

A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. The substance showed no evidence of systemic availability or toxicity in an acute oral or aerosol inhalation study. In a subacute (OECD 407) and a subchronic (OECD 408) study mild kidney effects (cortical tubular vacuolation) were seen at 1000 mg/kg. These findings were considered to be due to a storage process, and were shown to be be reversible in a two-weeks post exposure recovery in the subacute study. The DNEL derivation based on a NOAEL of 200 mg/kg bw/day with only mild effects at the next higher dose of 1000 mg/kg bw/day is already very conservative, therefore no correction for remaining interspecies differences has to be done, resulting in a factor 1.

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

Justification:

The database has a good quality, taking into account completeness, consistency and the standard information requirements, therefore the default factor of 1 applies.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified