Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

24.7 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 234 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study is available. Therefore, the DNEL is derived on basis of an OECD TG 422 toxicity study performed in the rat. This oral NOAEL of 1000 mg/kg bw/day for rats was converted to the corresponding air concentration using a standard breathing volume for the rat of 0.38 m3 /kg (for 8 hours exposure of workers). The resulting air concentration was additionally corrected for the difference between basal caloric demand and caloric demand under light activity. This correction factor derives from the inhalative volumes in 8 hours under the respective conditions (6.7 m3 for base level, 10 m3 for light activity). See "Additional Information" for more details.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to 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:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 400 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to 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:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:

An OECD TG 422 study with the target substance Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is available. Here, daily oral administration of the test item to Wistar rats did not elicit any signs of reproductive and developmental toxicity up to the highest dose tested. The NOAEL for systemic toxicity, developmental toxicity and fertility was considered to be 1000 mg/kg bw/day. This NOAEL is used as PoD for DNEL derivation.

Step 1:PoD: NOAEL = 1000 mg/kg bw/day

Step 2:Modification of PoD:

Standard respiratory volume, human (sRVhuman): 6.7 m3

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m3

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human):50%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 1000 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x (7/5)

= 1234 mg/m3

Step 3: Overall AF= 50

Intraspecies AF (workers): 5

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study performed with the test item was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

Whole database AF: 1

The OECD TG 422 toxicity study was conducted according to 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.

In conclusion, long term systemic inhalation DNEL, workers = 24.7 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

Due to the extremely low vapour pressure (2.1E-7 Pa at 20 °C and 3.73E-7 Pa at 25 °C) of Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate, inhalation exposure is not considered as relevant. Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is unlikely to be available as a vapor to a large extent. Therefore, no DNEL was derived.

Long term & acute, local DNEL- exposure via inhalation (workers)

A DNEL long term & acute - local effects is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008.Therefore, no local irritation or sensitisation of the respiratory system is expected.

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 1000 mg/kg bw/day derived from an OECD TG 422 study performed with the target was used as the PoD.

Step 1: PoD: NOAEL = 1000 mg/kg bw/day

Step 2: Modification into a correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

= 1000 mg/kg bw/day x (7/5)

= 1400 mg/kg bw/day

Step 3: Overall AF= 200

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Dose-response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

In conclusion, long term systemic dermal DNEL, workers = 7 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

No data for the classification and labelling of the test substance for acute dermal toxicity is available. The substance is not classified for acute oral toxicity, therefore no adverse result for dermal toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8).

Long term & acute, local DNEL- dermal exposure (workers)

DNELs for long term & acute - local effects are not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008.

Hazard to the eye-local effects (workers)

The test item is not classified for eye damage according to Regulation (EC) No 1272/2008 (CLP). Therefore, no hazard has been identified.

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.35 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

434.8 mg/m³

Explanation for the modification of the dose descriptor starting point:

No repeated dose inhalation toxicity study is available. The DNEL is derived on basis of an OECD TG 422 study. This oral NOAEL for rats was converted to the corresponding air concentration using a standard breathing volume for the rat of 1.15 m3/kg for 24 hours exposure (see "Additional Information").

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to 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:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 422 toxicity study performed with the test item was conducted according to 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:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

400

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

4

Justification:

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the relatively homogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The study according OECD TG 422 was conducted according to 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:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Inhalation

Long term, systemic DNEL – exposure by inhalation (general population)

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:

An OECD TG 422 study with Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is available. Here, daily oral administration of the test item to Wistar rats did not elicit any signs of reproductive and developmental toxicity up to the highest dose tested. The NOAEL for systemic toxicity, developmental toxicity and fertility was considered to be 1000 mg/kg bw/day. This NOAEL is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 1000 mg/kg bw/day

Step 2: Modification of PoD:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)

Corrected NOAEC (inhalation) for general population:

= 1000 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 434.8 mg/m3

Step 3: Overall AF= 100

Intraspecies AF (General population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

Whole database AF: 1

The OECD TG 422 toxicity study was conducted according to 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.

In conclusion, long term systemic inhalation DNEL, general population = 4.35 mg/m3

Acute, systemic DNEL- exposure via inhalation (general population)

Due to the extremely low vapour pressure (2.1E-7 Pa at 20 °C and 3.73E-7 Pa at 25 °C) of Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate, inhalation exposure is not considered as relevant. Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is unlikely to be available as a vapor to a large extent. Therefore, no DNEL was derived.

Long term, local DNEL- exposure via inhalation (general population)

A DNEL long term & acute - local effects is not established because the substance is not classified dangerous for skin/eye irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008. Therefore, no local irritation or sensitisation of the respiratory system is expected.

Dermal

Long term, systemic DNEL- exposure via dermal route (general population)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The NOAEL of 1000 mg/kg bw/day derived from an OECD TG 422 study performed with Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate was used as the PoD.

Step 1:PoD: NOAEL= 1000 mg/kg bw/day

Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h/7 d, 24h general population

Step 2:Overall AF= 400

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

In conclusion, long term systemic dermal DNEL, general population = 2.5 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

No data for the classification and labelling of the test substance for acute dermal toxicity is available. The substance is not classified for acute oral toxicity, therefore no adverse result for dermal toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8).

Long term & acute, local DNEL- dermal exposure (general population)

DNELs for long term & acute - local effects are not established because the substance is not classified dangerous for skin irritation/corrosion and skin sensitisation according to Regulation EC No 1272/2008.

Oral

Long term, systemic DNEL- exposure by oral route (general population)

A study according OECD TG 422 with Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate is available. Here, daily oral administration of the test item to Wistar rats did not elicit any signs of systemic, reproductive or developmental toxicity up to the highest dose tested. The NOAEL for systemic toxicity, developmental toxicity and fertility was considered to be 1000 mg/kg bw/day. This NOAEL is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 1000 mg/kg bw/day

Step 2:Overall AF= 400

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric scaling

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 4

The exposure duration of the OECD TG 422 study was 56 days for females and for males. In comparison to a subacute 28-day study the OECD TG 422 study provides additional information on fertility and developmental toxicity, which justifies the Assessment factor of 4.

In conclusion, long term systemic oral DNEL, general population= 2.5 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute oral toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

Hazard to the eye-local effects (general population)

The test item is not classified for eye damage according to Regulation (EC) No 1272/2008 (CLP).

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterization, Version 3.0, May 2016

Registration Dossier

Registration Dossier

Diss Factsheets

Reaction mass of calcium 2,6-bis(3-carboxylatopropanamido)hexanoate and isomers of calcium amino-(3-carboxylatopropanamido)hexanoate

Toxicological Summary

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

Workers - Hazard for the eyes

Local effects

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Acute/short term exposure

General Population - Hazard via oral route

Systemic effects

Long term exposure

DNEL related information

Acute/short term exposure

DNEL related information

General Population - Hazard for the eyes

Local effects

Additional information - General Population