Tri-alkyl Quat

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 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):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

25 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 (start 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:

1

Justification:

No additional assessment factor for duration extrapolation has to be applied as a chronic study is used as starting 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 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 database is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

No additional factor for remaining uncertainties is required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.14 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):

17.5

Modified dose descriptor starting point:

NOAEL

Value:

20 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by dermal route. Dermal absorption is anticipated to be 50 % of oral absorption. For details, please refer to the discussion.

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:

1

Justification:

No additional factor is required as a chronic study was used as starting point.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The recommended factor for allometric scaling from dog to human is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for 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:

No additional factor is required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.42 mg/kg bw/day

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

Explanation for the modification of the dose descriptor starting point:

see long-term systemic dermal DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.01 mg/cm²

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3.2

Dose descriptor:

other: NOAEL

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:

1

Justification:

No additional assessment factor for duration extrapolation has to be applied (local effects).

AF for interspecies differences (allometric scaling):

1

Justification:

Since the mechanism (direct chemical reactivity with cell membranes) of skin irritation/corrosion is considered to be the same in experimental animals and in human, no inter-species AF should be applied to the NOEC (in accordance with “Guidance on information requirements and chemical safety assessment, chapter R8: Characterisation of dose[concentration]-response for human health”, November 2012).

AF for other interspecies differences:

1

Justification:

No additional AF for interspecies differences is required.

AF for intraspecies differences:

3.2

Justification:

The chemical reactivity is the principle concern in this case. Therefore, for the intraspecies AF only 3.2 (3.16 ~3.2) for the toxicodynamic variability (in accordance with “Guidance on information requirements and chemical safety assessment, chapter R8: Characterisation of dose[concentration]-response for human health”, November 2012) was applied.

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:

No additional factor is required.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

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 is performed under consideration of the recommendations of ECHA. 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.

 

Workers – Hazard via inhalation route

 

Long term systemic DNEL, worker, inhalation route

Calculation of dose descriptor

 

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

For risk characterization an inhalation NOAEC was derived by route to route extrapolation.

The oral NOAEL of 10 mg/kg bw/day, obtained from a chronic repeated dose toxicity testing with a read across-substance in dogs was considered as key value for the chemical safety assessment and therefore most relevant starting point.

 

Step 2: Modification into a correct starting point:

In a first step the oral NOAEL was transferred to humans with a factor of 1.4 for allometric scaling from dogs. For worker a NOEC long-term, inhalation was calculated assuming 70 kg per person, 8h light activity (10 m³ breathing volume), and 50 % absorption via oral route and 100 % absorption via inhalatory route.

NOEC (Worker) inhalation = 10 mg/kg bw/day * 1/1.4 *70 kg * 1/10 m³ * 50 % Abs, (oral) / 100 % Abs, (inhal) = 25 mg/m³

 

Step 3: Use of assessment factors: 12.5

Interspecies: no allometric scaling factor is applied because a oral-to-inhalation route extrapolation is performed.

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

 

In conclusion the long term systemic inhalation DNEL workers was calculated to be 2 mg/m³ bw/day.

 

Short term acute inhalation DNEL, worker

 

Due to the low vapour pressure of the substance no peak exposure is to be expected and therefore no acute systemic worker-DNEL for the inhalatory route has to be derived (in accordance with "Guidance on information requirements and chemical safety assessment", Chapter R8, November 2012).

 

Local effects

 

No data on local toxicity after inhalation is available. The substance is classified into skin irritation/corrosion cat. 1B according to Regulation (EC) No 1272/2008 (CLP). Therefore local mucosal membrane damage cannot be excluded (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). The substance is therefore allocated to the high hazard band. A qualitative risk assessment is conducted (according to "Guidance on information requirements and chemical safety assessment part E: risk characterisation", Nov. 2012).

 

Workers – Hazard via dermal route

 

Long term systemic DNEL, worker, dermal route

Calculation of dose descriptor

 

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

For risk characterization a dermal NOAEC was derived by route to route extrapolation.

The oral NOAEL of 10 mg/kg bw/day, obtained from a chronic repeated dose toxicity testing with a read across-substance in dogs was considered as key value for the chemical safety assessment and therefore most relevant starting point.

 

Step 2: Modification into a correct starting point:

An absorption rate of 50 % through skin was deduced, as dermal uptake of quaternary ammonium ions can be slowed due to their reactivity and binding to skin components (in accordance with “Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance”). In conclusion, the dermal NOAEL = oral NOAEL x [ABS oral dog/ABS dermal human] = 10 mg/kg bw/day x (100/50)= 20 mg/kg bw/day

 

Step 3: Use of assessment factors: 17.5

Interspecies: allometric scaling (dog to human): 1.4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

In conclusion the long term systemic inhalation DNEL workers was calculated to be 1.14 mg/kg bw/day.

 

Acute short term DNEL, worker, dermal route

 

The substance is classified for acute dermal toxicity into cat. 3 according to Regulation (EC) No 1272/2008 (CLP) and therefore the DNEL for acute toxicity was derived by multiplying the long-term DNEL with a default factor of 3 (according to "Guidance on information requirements and chemical safety assessment", chapter R8, November 2012).

 

Local effects

 

Long term local DNEL, worker, dermal route

 

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

For risk characterization the local dermal NOAEC was derived from the NOAEL of the read across substance obtained in a 2 weeks skin irritation study in rats considering the different Molecular Weights (MW) of the target substance and of the source substance (362.1 g/mol). For this calculation, a molecular weight of 207.8 g/mol was used for the target substance. The following formula has been applied:

NOAEL(target substance) = (NOAEL(source substance)/ MW(source substance)) x MW(target substance)= (6mg/kg bw/day /362.1) x 207.8= 4.5 mg/kg bw/day

Step 2: Modification into a correct starting point:

It was assumed that the treated body surface was 10 %. The total surface body of rat (male and female) is 400 cm2 and the mean body weight is 300 g. Assuming that 10 % of the body surface has been exposed to the test substance, the resulting exposed area is of 40 cm2.

For the characterization of the risk due to the local dermal effects a NO(A)EC (expressed in mg/cm2) was derived according to the following formula:

NOAEC in mg /cm2 =( Total dose applied in mg)/( Treated surface in cm2) =

(average animal weight in kg * dose in mg kg bw)/ (treated surface area in cm2)

NOAEC = (0.3 kg x 4.5 mg/kg bw/day) / 40cm2 = 0.034 mg/cm2

Step 3: Use of assessment factors: 3.2

Interspecies: Since the mechanism (direct chemical reactivity with cell membranes) of skin irritation/corrosion is considered to be the same in experimental animals and in human, no inter-species AF should be applied to the NOEC (in accordance with “Guidance on information requirements and chemical safety assessment, chapter R8: Characterisation of dose[concentration]-response for human health”, November 2012).

Intraspecies AF (worker): Regarding intra-species differences it could be acceptable to lower the default factor, given that chemical reactivity is the principle concern. Therefore, for the intraspecies AF only 3.16 for the toxicodynamic variability (in accordance with “Guidance on information requirements and chemical safety assessment, chapter R8: Characterisation of dose[concentration]-response for human health”, November 2012) could be taken into consideration (3.16 ~3.2).

Therefore, for the dermal route the overall AF turns out to be 3.2

In conclusion the long term local dermal DNEL workers was calculated to be 0.01 mg/cm2 /day.

 

Short term local DNEL, worker, dermal route

 

The substance is classified as skin corrosive, cat. 1B according to Regulation (EC) No 1272/2008 (CLP) and therefore associated to the high Hazard Band. A qualitative risk assessment is conducted (according to "Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Characterisation", Nov. 2012).

 

Worker – Hazard for the eyes

 

The substance is classified for skin corrosion into cat. 1B and labelled with H314 (Causes severe skin burns and eye damage) according to Regulation (EC) No 1272/2008 (CLP) and therefore associated to the medium Hazard Band. A qualitative risk assessment is conducted (according to "Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Charactersisation", Nov. 2012).

 

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. November 2012.

 

- ECHA (2010). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2012.

 

- 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:

no hazard identified

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:

no hazard identified

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:

no hazard identified

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