Tris(2-hydroxyethyl)methylammonium methyl sulphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.3 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):

25

Modified dose descriptor starting point:

NOAEC

Value:

358.3 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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

40.6 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

Modified dose descriptor starting point:

NOAEL

Value:

4 064 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 properties of the substance, dermal absorption 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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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

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

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Acute, systemic DNEL

Short term DNELs are not required as the acute toxicity of the test substance is low. The test substance is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation 1272/2008/EC (CLP), based on the test data for acute oral and dermal toxicity. For acute inhalative toxicity no adequate test data is available to decide on classification and labelling. A low inhalation hazard can be assumed based on the inhalation risk test performed (No mortality when exposed to the volatile components at 20 °C for 8 hours).

 

Acute/longterm, local

The test substance is not classified and labelled as irritating to eyes and skin. Furthermore it is not considered as sensitising based on a LLNA assay.

 

Long term, systemic DNEL

Occupational exposure to the test substance occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two long-term DNELs are calculated for workers.

Exposure by inhalation

 

Step 1: Selection of the relevant dose descriptor (starting point):

In order to derive a long-term inhalation DNEL, an inhalation NOEC was derived from NOEL oral value (determined in a 90-d repeated dose toxicity study with rats), as no repeated dose inhalation study was available. Oral NOEL of 406.4 mg/kg bw/day was converted to an inhalation NOEC, assuming 100% absorption via the lung and 50 % absorption via the oral route.

 

Step 2: Modification into a correct starting point:

The oral NO(A)EL was converted into an inhalation NO(A)EC according to the following formula assuming a daily exposure period of 8 hours during light activity:

 

Relevant dose descriptor (NO(A)EL): 406.4 mg/kg bw/day

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

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

= 406.4 mg/kg bw/day × (1 / 0.38 m³/kg bw/day) × 0.5 × (6.7 m³/10 m³)

= 358.3 mg/m³

 

Step 3: Use of assessment factors: 25

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 2

 

In conclusion, long term systemic inhalation DNEL, workers = 14.3 mg/m³

 

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

In order to derive a long-term dermal DNEL, a dermal NOEL was derived from NOEL oral value (determined in a 90-d repeated dose toxicity study with rats), as no repeated dose dermal study was available. The oral NOEL of 406.4 mg/kg bw/day was used as starting point.

 

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test substance (based on Guidance on information requirements and chemical safety assessment, R. 7C, 2014, Chapter R 7.12):

Dermal absorption is supposed to be low regarding the molecular weight of 275.32 g/mol and the high water solubility. The barrier function of the skin for ionic substances further decreases the penetration of the test substance. In addition, the results of the acute dermal toxicity support a low absorption via dermal route. Therefore, oral NOEL of 406.4 mg/kg bw/day was converted to a dermal NOEL, considering a conservative 10 % absorption through the skin.

 In conclusion, dermal NO(A)EL = 406.4 x (100/10) = 4064 mg/kg bw/d.

 

Step 3: Use of assessment factors: 100

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 2

 

In conclusion, long term systemic dermal DNEL, workers = 40.6 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.

 

- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 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:

176.7 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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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 more heterogenous 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

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:

20.3 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:

4 064 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 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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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 more heterogenous 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

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:

2.03 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:

406.4 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required since a repeated dose oral toxicity study is available.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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 more heterogenous 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

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Acute, systemic DNEL

Short term DNELs are not required as the acute toxicity of the test substance is low. The test substance is not classified and labelled for acute systemic toxicity, according to Directive 67/548/EEC (DSD) and Regulation 1272/2008/EC (CLP), based on the test data for acute oral and dermal toxicity. For acute inhalative toxicity no adequate test data is available to decide on classification and labelling. A low inhalation hazard can be assumed based on the inhalation risk test performed (No mortality when exposed to the volatile components at 20 °C for 8 hours).

 

Acute/longterm, local

The test substance is not classified and labelled as irritating to eyes and skin. Furthermore it is not considered as sensitising based on a LLNA assay.

 

Long term, systemic DNEL

 

Exposure by inhalation

 

Step 1: Selection of the relevant dose descriptor (starting point):

In order to derive a long-term inhalation DNEL, an inhalation NOEC was derived from NOEL oral value (determined in a 90-d repeated dose toxicity study with rats), as no repeated dose inhalation study was available. Oral NOEL of 406.4 mg/kg bw/day was converted to an inhalation NOEC, assuming 100% absorption via the lung and 50 % absorption via the oral route.

 

Step 2: Modification into a correct starting point:

Relevant dose descriptor (NO(A)EL): 406.4 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 1.15 m³/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

 

Corrected inhalatory NOAEC for general population

= 406.4 mg/kg bw/day × (1 / 1.15 m³/kg bw/day) × 0.5

= 176.7 mg/m³

 

Step 3: Use of assessment factors: 50

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 2

 

In conclusion, long term systemic inhalation DNEL, general population = 3.5 mg/m³

 

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

In order to derive a long-term dermal DNEL, a dermal NOEL was derived from NOEL oral value (determined in a 90-d repeated dose toxicity study with rats), as no repeated dose dermal study was available. The oral NOEL of 406.4 mg/kg bw/day was used as starting point.

 

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test substance (based on Guidance on information requirements and chemical safety assessment, R. 7C, 2014, Chapter R 7.12):

Dermal absorption is supposed to be low regarding the molecular weight of 275.32 g/mol and the high water solubility. The barrier function of the skin for ionic substances further decreases the penetration of the test substance. In addition, the results of the acute dermal toxicity support a low absorption via dermal route. Therefore, oral NOEL of 406.4 mg/kg bw/day was converted to a dermal NOEL, considering a conservative 10 % absorption through the skin.

 In conclusion, dermal NO(A)EL = 406.4 x (100/10) = 4064 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 (general population): 10

Exposure duration AF: 2

 

In conclusion, long term systemic dermal DNEL, general population = 20.3 mg/kg bw/day.

 

Oral exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

In order to derive a long-term oral DNEL, an oral NOEL determined in the 90-d repeated dose toxicity study with rats was identified as the relevant dose descriptor (406.4 mg/kg bw/day).

 

Step 2: Use of assessment factors: 200

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 2

 

In conclusion, long term systemic oral DNEL, general population = 2.03 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.

 

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics.