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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.18 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
42.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
262.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
according to ECHA guideance  
AF for dose response relationship:
1
Justification:
already considered in point of departure correction
AF for differences in duration of exposure:
3.4
Justification:
according to BATKE et al. see discussion
AF for interspecies differences (allometric scaling):
1
Justification:
already considered in point of departure correction
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
5
Justification:
rat -> worker according to ECHA R8 guideance
AF for the quality of the whole database:
1
Justification:
see discussion
AF for remaining uncertainties:
2.5
Justification:
according to ECHA R8 guideance
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:
1.76 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
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
AF for dose response relationship:
1
Justification:
already considered in point of departure correction
AF for differences in duration of exposure:
3.4
Justification:
according to BATKE et al. see discussion
AF for interspecies differences (allometric scaling):
1
Justification:
already considered in point of departure correction
AF for other interspecies differences:
4
Justification:
see discussion
AF for intraspecies differences:
5
Justification:
rat -> worker according to ECHA R8 guideance
AF for the quality of the whole database:
1
Justification:
see discussion
AF for remaining uncertainties:
2.5
Justification:
according to ECHA R8 guideance
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

DNEL derivation for Octadecanoic acid, sulfo-, potassium salt according to ECHA and ECETOC guidance documents

 

Based on a comparison of the different available studies the most reliable and relevant NOAEL for the derivations of a DNEL can be obtained from the following studies:

 

Most sensitive record for systemic effects is:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF SE, 2015) conducted with Octadecanoic acid, sulfo-, potassium salt was identified as the appropriate starting point for DNEL derivation.NOAEL, (f/m, systemic, oral, rats):150 mg/kg bw.

The 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., as therethere is no adequate subacute/subchronic studies for dermal or inhalation available.

1      Worker:

1.1     Inhalation (worker)

1.1.1     Point of departure correction (inhalation, worker)

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volumes of rats versus humans. The resulting corrected starting point for inhalation DNEC derivation for workers is equal to 262.5 mg/m³. 100% absorption is assumed.        

Point of departure correction: NOAEL oral -> NOAEC human (8h worker)

 

NOAEC human (8h worker) = oral NOAEL rat/ sRVrat(AS)*(bw human/wRV) = 150/4 x 70/10 = 262.5 mg / m3 / 24h  

1.1.2     Assessment factors (AF) (inhalation, worker)

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

Parameter

AF (ECHA)

Justification

Interspecies (rat -> human)

1

Already considered in starting point correction

Interspecies (remaining differences)

2.5

Standard factor as outlined in REACh Guidance document R.8  

Intraspecies (worker)

5

Standard factor as outlined in REACh Guidance document R.8  

Exposure duration

3.4

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose 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.

Route to route (oral- inhalation)

1

Already considered in starting point correction

Dose response issues

1

NOAEL ->NOAEL

Quality

1

Reliability 1, well documented GLP-study

SUM AF

42.5

 

1.1.3     Calculation of DNEC (inhalation, worker)

DNEC= corrected NOAEC/SUM (AF) = 262.5/42.5 = 6.18 mg/m3

 

1.2     Dermal (worker)

1.2.1     Point of departure correction (dermal, worker)

The point of departure was modified to get the corrected starting point for DNEL derivation. As the acute data shows that acute dermal toxicity is considerably lower than acute oral toxicity it is assumed that dermal absorption is considerably lower than oral uptake. The NOAEL was therefore corrected by a factor of 2.The inclusion of factor 2 means that 50% (instead of 100%) absorption is assumed for dermal absorption, and 100% for oral, which resulted in a corrected starting point for DNEL derivation for worker of 300 mg/kg bw/day.

Point of departure correction: NOAEL oral,rat -> NOAEL dermal, human

 

NOAEL human (worker) = oral NOAEL rat * (ABSoral,rat/ ABSdermal,human)= 150 * (100%/50%) = 300 mg/kg 

1.2.2     Assessment factors (AF) (dermal, worker)

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

Parameter

AF (ECHA)

Justification

Interspecies (rat -> human)

4

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

Interspecies (remaining differences)

2.5

Standard factor as outlined in REACh Guidance document R.8  

Intraspecies (worker)

5

Standard factor as outlined in REACh Guidance document R.8  

Exposure duration

3.4

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose 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.

Route to route (oral- dermal)

1

Already considered in starting point correction

Dose response issues

1

NOAEL -> NOAEL

Quality

1

Reliability 1, well documented GLP-study

SUM AF

170

 

 

1.2.3     Calculation of DNEL (dermal, worker)

DNEL= corrected NOAEL/SUM (AF) = 300/170 = 1.76 mg/kg

 

1.3     Oral (worker)

 

A long-term, oral systemic DNEL for worker is not relevant.

 

2      Overview derived DNEL/C´s

 

DNEC (inhalation, worker)                6.18 mg/m3

DNEL (dermal, worker)                     1.76 mg/kg bw/d

DNEL (oral, worker)                          not relevant

3. References

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, MessingerH, 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:
1.54 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
85
Modified dose descriptor starting point:
NOAEC
DNEL value:
13.25 mg/m³
Explanation for the modification of the dose descriptor starting point:
see discussion
AF for dose response relationship:
1
Justification:
already considered in point of departure correction
AF for differences in duration of exposure:
3.4
Justification:
according to BATKE et al. see discussion
AF for interspecies differences (allometric scaling):
1
Justification:
already considered in point of departure correction
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
10
Justification:
rat -> general poplulation according to ECHA R8 guideance
AF for the quality of the whole database:
1
Justification:
see discussion
AF for remaining uncertainties:
2.5
Justification:
according to ECHA R8 guideance
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:
0.88 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
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
AF for dose response relationship:
1
Justification:
already considered in point of departure correction
AF for differences in duration of exposure:
3.4
Justification:
according to BATKE et al. see discussion
AF for interspecies differences (allometric scaling):
4
Justification:
already considered in point of departure correction
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
10
Justification:
rat -> general popluation according to ECHA R8 guideance
AF for the quality of the whole database:
1
Justification:
see discussion
AF for remaining uncertainties:
2.5
Justification:
according to ECHA R8 guideance
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.44 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
DNEL value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
see discussion
AF for dose response relationship:
1
Justification:
already considered in point of departure correction
AF for differences in duration of exposure:
3.4
Justification:
according to BATKE et al. see discussion
AF for interspecies differences (allometric scaling):
4
Justification:
already considered in point of departure correction
AF for other interspecies differences:
1
Justification:
see discussion
AF for intraspecies differences:
10
Justification:
rat -> general popluation according to ECHA R8 guideance
AF for the quality of the whole database:
1
Justification:
see discussion
AF for remaining uncertainties:
2.5
Justification:
according to ECHA R8 guideance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

DNEL derivation for Octadecanoic acid, sulfo-, potassium salt according to ECHA and ECETOC guidance documents

 

Based on a comparison of the different available studies the most reliable and relevant NOAEL for the derivations of a DNEL can be obtained from the following studies:

 

Most sensitive record for systemic effects is:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (BASF SE, 2015) was

identified as the appropriate starting point for DNEL derivation.NOAEL, (f/m, systemic, oral, rats):150 mg/kg bw

The 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., as therethere is no adequate subacute/subchronic studies for dermal or inhalation available.


1      General population

1.1     Inhalation (general)

1.1.1     Point of departure correction (inhalation, general)

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volumes of rats versus humans. The resulting corrected starting point for inhalation DNEC derivation for the general population is 131.25 mg/m³.100% absorption is assumed.

 

Point of departure correction NOAEL oral -> NOAEC human (24h):

 

NOAEC human (24h general) = oral NOAEL rat/ sRVrat(AS)*(bw human/wRV) = 150/4 x 70/20 = 131.25 mg / m3 / 24h

1.1.2     Assessment factors (AF) (inhalation, general)

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

Parameter

AF (ECHA)

Justification

Interspecies (rat -> human)

1

Already considered in starting point correction

Interspecies (remaining differences)

2.5

Standard factor as outlined in REACh Guidance document R.8  

Intraspecies (general)

10

Standard factor as outlined in REACh Guidance document R.8  

Exposure duration

3.4

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose 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.

Route to route (oral- inhalation)

1

Already considered in allometric scaling factor for starting point correction

Dose response issues

1

NOAEL -> NOAEL

Quality

1

Reliability 1, well documented GLP-study

SUM AF

85

 

 

1.1.3     Calculation of DNEC (inhalation, general)

DNEC= corrected NOAEC/SUM (AF) = 131.25/85 = 1.54 mg/m3

 

1.2     Dermal (general)

1.2.1     Point of departure correction (dermal, general)

The point of departure was modified to get the corrected starting point for DNEL derivation. As the acute data shows that acute dermal toxicity is considerably lower than acute oral toxicity it is assumed that dermal absorption is considerably lower than oral uptake. The NOAEL was therefore corrected by a factor of 2.The inclusion of factor 2 means that 50% (instead of 100%) absorption is assumed for dermal absorption, and 100% for oral, which resulted in a corrected starting point for DNEL derivation for worker of 250 mg/kg bw/day.

Point of departure correction: NOAEL oral,rat -> NOAEL dermal, human

 

NOAEL human (worker) = oral NOAEL rat * (ABSoral,rat/ ABSdermal,human) = 150 * (100%/50%) = 300 mg/kg 

1.2.2     Assessment factors (AF) (dermal, general)

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

Parameter

AF (ECHA)

Justification

Interspecies (rat -->human)

4

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

Interspecies (remaining differences)

2.5

Standard factor as outlined in REACh Guidance document R.8  

Intraspecies (worker)

10

Standard factor as outlined in REACh Guidance document R.8  

Exposure duration

3.4

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose 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.

Route to route (oral- dermal)

1

Already considered in starting point correction

Dose response issues

1

NOAEL --> NOAEL

Quality

1

Reliability 1, well documented GLP-study

SUM AF

340

 

 

1.2.3     Calculation of DNEL (dermal, general)

DNEL= corrected NOAEL/SUM (AF) = 300/340 = 0.88 mg/m3

 

1.3     Oral (general)

1.3.1    Point of departure correction (oral, general)

 

No modification for oral dose descriptor necessary as there is an adequate study available: NOAEL (oral, rat) -> NOAEL (oral, rat)

 

1.3.2     Assessment factors (AF) (oral, general)

 

The NOAEL of 150 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:

 

Parameter

AF (ECHA)

Justification

Interspecies (rat ->human)

4

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

Interspecies (remaining differences)

2.5

Standard factor as outlined in REACh Guidance document R.8  

Intraspecies (general)

10

Standard factor as outlined in REACh Guidance document R.8  

Exposure duration

3.4

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose 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.

Route to route (oral- oral)

1

Not necessary (oral-oral)

Dose response issues

1

NOAEL à NOAEL

Quality

1

Reliability 1, well documented GLP-study

SUM AF

340

 

 

1.3.3     Calculation of DNEL (oral, general)

DNEL=  NOAEL/SUM (AF) = 150/340 = 0.44 mg/m3

 

1.4     Oral short-term-systemic effects:

The long-term oral DNEL for systemic effects will also be sufficiently protective for short-term oral systemic effects. Therefore no DNEL was derived.

2      Overview derived DNEL/C´s

 

DNEC (inhalation, general)                1.54 mg/m3

DNEL (dermal, general)                    0.88 mg/kg bw/d

DNEL (oral, general)                          0.44 mg/kg bw/d

3. References

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, MessingerH, 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.