Potassium N,N-dimethylglycinate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18.04 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

Modified dose descriptor starting point:

NOAEC

Value:

902.21 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

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:

An extrapolation factor of 4 was used because the DNEL was derived from a OECD 422 with a treatment duration of 29 days (males) up to 53 days (females).

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:

Recommended AF for other interspecies differences.

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 quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

51.17 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

Modified dose descriptor starting point:

NOAEL

Value:

10 234 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical and toxic properties of the substance, dermal absoption is anticipated to be 10 % of oral absorption.

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:

An extrapolation factor of 4 was used because the DNEL was derived from a OECD 422 with a treatment duration of 29 days (males) up to 53 days (females).

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:

Recommended AF for other interspecies differences.

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 quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General
DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012).
 
Acute, systemic DNEL
The test substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, the derivation of a DNEL for acute/short term exposure is not required.
 
Acute/long term DNEL for local effects
Respiratory irritation: No short-term or long-term inhalation study is available. Based on the results of an acute eye irritation study, the test substance is classified for eye irritation cat. 1  according to Regulation (EC) No 1272/2008 (CLP) and associated to the moderate hazard band. In conclusion mucosal membrane damage has been identified (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012). Thus, a qualitative assessment is conducted.

Skin irritation/corrosion: The test substance is not classified for skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.
 
Eye irritation: The test substance is classified for eye irritation cat. 1 according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, a qualitative assessment is conducted.
 
Long term, systemic DNEL
Occupational exposure to the test substance occurs mainly by oral and dermal route. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor", "dose-response factor" and “remaining uncertainties” are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.
 
Exposure by inhalation
Step 1: Selection of the relevant dose descriptor (starting point):
For risk characterization an inhalation NOAEC was derived by route to route extrapolation. The OECD TG 422 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 731 mg/kg bw/day.
 
Step 2: Modification into a correct starting point:
Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting point). This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).
 
Relevant dose descriptor (NOAEL): 731 mg/kg bw/day
Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d
Frequency of exposure used in study: 7 days/week
Frequency of worker: 5 days/week
Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5
Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³
Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³
 
Corrected inhalatory NOAEC for workers
= 731 mg/kg bw/d × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³) x 7/5
= 902.21 mg/m³ 
 
Step 3: Use of assessment factors: 50
Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 5
Exposure duration AF: 4 (29 - 53 days)
 
In conclusion, long term systemic inhalation DNEL, workers = 18.04 mg/m³
 
Dermal exposure
Step 1: Selection of the relevant dose descriptor (starting point):
The OECD TG 422 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 731 mg/kg bw/day.
 
Step 2: Modification of the starting point:
A worker DNEL (long-term dermal exposure) is derived. Based on physico-chemical (MW = 141.2 g/mol, log Kow = -2.91) and toxic properties of the test substance dermal absorption is anticipated to be low. The test substance is not classified as skin irritant or skin sensitizer and therefore no damage to the skin may enhance penetration. Thus, a dermal absorption of 10 % of oral absorption is assumed as worst case.

Relevant dose descriptor (NOAEL): 731 mg/kg bw/day
Frequency of exposure used in study: 7 days/week
Frequency of exposure of the worker: 5 days/week
ABS (oral rat): 100 %
ABS (dermal human): 10 %
 
Corrected dermal NOAEL for worker:
= 731 mg/kg bw/d x (100/10) x 7/5 = 10234 mg/kg bw/d. 
 
Step 3: Use of assessment factors: 200
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 2.5
Intraspecies AF (worker): 5
Exposure duration AF: 4 (29 - 53 days)
 
In conclusion, long term systemic dermal DNEL, workers = 51.17 mg/kg bw/day
 
References
(not included as endpoint study record) 
- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1 ECHA-2010-G-19 –EN. 
- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. Version 2. ECHA-14 -G-06 -EN. 
- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.71 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):

100

Modified dose descriptor starting point:

NOAEC

Value:

270.74 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting point).

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:

An extrapolation factor of 4 was used because the DNEL was derived from a OECD 422 with a treatment duration of 29 days (males) up to 53 days (females).

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:

Recommended AF for other interspecies differences.

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 quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

18.28 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

7 310 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical and toxic properties of the substance, dermal absoption is anticipated to be 10 % of oral absorption.

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:

An extrapolation factor of 4 was used because the DNEL was derived from a OECD 422 with a treatment duration of 29 days (males) up to 53 days (females).

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:

Recommended AF for other interspecies differences.

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 quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.83 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

731 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:

An extrapolation factor of 4 was used because the DNEL was derived from a OECD 422 with a treatment duration of 29 days (males) up to 53 days (females).

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:

Recommended AF for other interspecies differences.

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 quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

General
DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012).
 
Acute, systemic DNEL
The test substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, the derivation of a DNEL for acute/short term exposure is not required.
 
Acute/long term DNEL for local effects
Respiratory irritation: No short-term or long-term inhalation study is available. Based on the results of an acute eye irritation study, the test substance is classified for eye irritation cat. 1  according to Regulation (EC) No 1272/2008 (CLP) and associated to the moderate hazard band. In conclusion mucosal membrane damage has been identified (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012). Thus, a qualitative assessment is conducted.

Skin irritation/corrosion: The test substance is not classified for skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, no qualitative assessment is conducted.
 
Eye irritation: The test substance is classified for eye irritation cat. 1 according to Regulation (EC) No 1272/2008 (CLP) based on the available experimental data. Therefore, a qualitative assessment is conducted.

Long term, systemic DNEL
Exposure to the test substance may occur via inhalation, dermal and oral route. Therefore three long-term DNELs are calculated for general population. In view of the data used for evaluation, the "quality of whole database factor", "dose-response factor" and “remaining uncertainties” are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.
 
Exposure by inhalation
Step 1: Selection of the relevant dose descriptor (starting point):
For risk characterization an inhalation NOAEC was derived by route to route extrapolation. The OECD TG 422 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 731 mg/kg bw/day.
 
Step 2: Modification into a correct starting point:
Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting point). This general population DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).
 
Relevant dose descriptor (NOAEL): 731 mg/kg bw/day
Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m³/kg bw/d
Frequency of exposure used in study: 7 days/week
Frequency of the general population: 7 days/week
Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5
 
Corrected inhalatory NOAEC for general population
= 731 mg/kg bw/d × 0.5 × (1 / 1.35 m³/kg bw/d) × 7/7
= 270.74 mg/m³ 
 
Step 3: Use of assessment factors: 100
Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC
Interspecies AF, remaining differences: 2.5
Intraspecies AF (general population): 10
Exposure duration AF: 4 (29 - 53 days)
 
In conclusion, long term systemic inhalation DNEL, general population = 2.71 mg/m³


Dermal exposure
Step 1: Selection of the relevant dose descriptor (starting point):
The OECD TG 422 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 731 mg/kg bw/day.
 
Step 2: Modification of the starting point:
Using a conservative approach, a DNEL for general population (long-term dermal exposure) is derived. Based on physico-chemical (MW = 141.2 g/mol, log Kow = -2.91) and toxic properties of the test substance dermal absorption is anticipated to be low. The test substance is not classified as skin irritant or skin sensitizer and therefore no damage to the skin may enhance penetration. Thus, a dermal absorption of 10 % of oral absorption is assumed as worst case.

Relevant dose descriptor (NOAEL): 731 mg/kg bw/day
Frequency of exposure used in study: 7 days/week
Frequency of exposure of the worker: 7 days/week
ABS (oral rat): 100 %
ABS (dermal human): 10 %
 
Corrected dermal NOAEL for worker:
= 731 mg/kg bw/d x (100/10) x 7/7 = 7310 mg/kg bw/d. 
 
Step 3: Use of assessment factors: 400
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 2.5
Intraspecies AF (general population): 10
Exposure duration AF: 4 (29 -53 days)
 
In conclusion, long term systemic dermal DNEL, general population = 18.28 mg/kg bw/day

Oral exposure
Step 1: Selection of the relevant dose descriptor (starting point): 
The OECD TG 422 study is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL in rats is 731 mg/kg bw/day.  

Step 2: Modification of the starting point: 
Not required 

Step 3: Use of assessment factors: 400 
Interspecies AF, allometric scaling (rat to human): 4
Interspecies AF, remaining differences: 2.5
Intraspecies AF (general population): 10
Exposure duration AF: 4 (29 - 53 days)

In conclusion, long term systemic dermal DNEL, general population = 1.83 mg/kg bw/day

References
(not included as endpoint study record) 
- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1 ECHA-2010-G-19 –EN. 
- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. Version 2. ECHA-14 -G-06 -EN. 
- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.