Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.778 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
67
Modified dose descriptor starting point:
NOAEC
Value:
52.9 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.778 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
68
Dose descriptor:
NOAEC
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
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:
0.176 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
170
Modified dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

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

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Worker:

Based on the available data,” Sulfonium compounds, C11-14-alkylbis(hydroxyethyl), 2-hydroxyethyl sulfates (salts)”, has to be considered as corrosive to skin and eyes (R34 according to Directive 67/548/EEC annex VI; Cat. 1C according to EC/1271/2008), harmful if swallowed (R22/Cat. 4 oral) and the substance may cause damage to organs through prolonged or repeated exposure (R48/22, STOT Repeated Cat. 2).As no dose response information for the local effects exists, the use of protective gloves and appropriate eye protection is mandatory whenever a potential for relevant ocular or dermal exposure exists.

The primary routes of anticipated industrial and professional exposure are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).

Inhalation long-term exposure – local effects (also covers systemic effects):

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (CiToxLAB Hungary, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for systemic and local toxicity was at 30 mg/kg bw/day. As the substance was severely irritating to the skin, an additional safety factor is applied to cover for any potentially occurring local effects on the respiratory tract (see below).

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 52.9 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

- Additional safety factor to cover for potential local effects (irritation) and remaining differences: 4  

 - Intraspecies factor: 5

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). In addition females were exposed for a longer period of time (at least 42 days instead of 28 days), a factor of 3.4 therefore is sufficient.

- Dose-response: 1

Total AF = 1 x 4 x 5 x 3.4 x 1 = 68

Based on this calculation the resulting DNEL is 0.778 mg/m³.

Dermal short-term and long-term exposure – local effects:

The substance is corrosive to skin and eyes. As no dose response information for these local effects exists, the use of protective gloves and appropriate eye protection is mandatory whenever a potential for relevant ocular or dermal exposure exists. The use of appropriate protective gloves will also sufficiently protect for any systemic effects.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (CiToxLAB Hungary, 2013) was identified as the appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/d for rats.

There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

-         Remaining differences: 2.5

Recommended in REACh Guidance document R.8 

-         Intraspecies factor: 5

Recommended in REACh Guidance document R.8 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). In addition females in which the observed effects on reproduction and development occurred were exposed for a longer period of time (at least 42 days instead of 28 days), a factor of 3.4 therefore is sufficient.

- Dose-response: 1

Total AF = 4 x 2.5 x 5 x 3.4 x 1 = 170

Based on this calculation the resulting DNEL is 0.176 mg/kg bw/day.

 

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.

 

 - Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

-ECHA (2008). REACh Guidance document R.8

-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs. Technical Report No. 110, October 2010.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.192 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
136
Modified dose descriptor starting point:
NOAEC
Value:
26.08 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.192 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
136
Dose descriptor:
NOAEC
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
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:
0.088 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
340
Modified dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
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)
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.088 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
340
Modified dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Justification:
see discussion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Consumer

Based on the available data,” Sulfonium compounds, C11-14-alkylbis(hydroxyethyl), 2-hydroxyethyl sulfates (salts)”, has to be considered as corrosive to skin and eyes (R34 according to Directive 67/548/EEC annex VI; Cat. 1C according to EC/1271/2008), harmful if swallowed (R22/Cat. 4 oral) and the substance may cause damage to organs through prolonged or repeated exposure (R48/22, STOT Repeated Cat. 2).As no dose response information for the local effects exists, the use of protective gloves and appropriate eye protection is mandatory whenever a potential for relevant ocular or dermal exposure exists.

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.

Inhalation long-term exposure – local effects (also covers systemic effects):

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (CiToxLAB Hungary, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for systemic toxicity was at 30 mg/kg bw/day. As the substance was severely irritating to the skin, an additional safety factor is applied to cover for any potentially occurring local effects on the respiratory tract (see below).

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 26.08 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

- Additional safety factor to cover for potential local effects (irritation) and remaining differences: 4  

- Intraspecies factor: 10

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). In addition females were exposed for a longer period of time (at least 42 days instead of 28 days), a factor of 3.4 therefore is sufficient.

- Dose-response: 1

Total AF = 1 x 4 x 10 x 3.4 x 1 = 136

Based on this calculation the resulting DNEL is 0.192 mg/m³.

Dermal short-term and long-term exposure – local effects:

The substance is corrosive to skin and eyes. As no dose response information for these local effects exists, the use of protective gloves and appropriate eye protection is mandatory whenever a potential for relevant ocular or dermal exposure exists. The use of appropriate protective gloves will also sufficiently protect for any systemic effects.

Dermal long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (CiToxLAB Hungary, 2013) was identified as the appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/d for rats.

There is no data available indicating that dermal uptake is considerably lower than oral uptake. The oral systemic long-term NOAEL was therefore considered appropriate for derivation of a dermal systemic long-term DNEL without further correction.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

-         Remaining differences: 2.5

Recommended in REACh Guidance document R.8 

-         Intraspecies factor: 10

Recommended in REACh Guidance document R.8 

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

Total AF = 4 x 2.5 x 10 x 3.4 x 1 x 1 = 340

Based on this calculation the resulting DNEL is 0.088 mg/kg bw/day.

Oral long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (CiToxLAB Hungary, 2013) was identified as the appropriate starting point for DNEL derivation for long-term oral exposure. The NOAEL for systemic toxicity was at 30 mg/kg bw/day.

The NOAEL of 800 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (1), intraspecies differences (10), exposure duration (3.4) (AF = 4 x 10 x 3.4 x 1 x 2.5 = 340).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 0.088 mg/kg bw/d for the general population.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

- Intraspecies factor: 10

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011). In addition females were exposed for a longer period of time (at least 42 days instead of 28 days), a factor of 3.4 therefore is sufficient.

- Dose-response: 1

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8

   

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.

 

- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

-ECHA (2008). REACh Guidance document R.8

-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.