Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
17.5
Modified dose descriptor starting point:
NOAEC
Value:
43.8 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:
1.4
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:
0.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
70
Modified dose descriptor starting point:
NOAEL
Value:
50 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:
1.4
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 2-Propyn-1-ol, polymer with ethylene oxide(CAS 25749-64-8) 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 408 study (90d study with extended investigation on reproduction parameter) (BASF 2018) was identified as the appropriate starting point for DNEL derivation.NOAEL, (f/m, systemic, oral, rats):25 mg/kg bw/d

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 43.8 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) = 25/4 x 70/10 = 43.8 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

1.4

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).

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

17.5

 

1.1.3     Calculation of DNEC (inhalation, worker)

DNEC= corrected NOAEC/SUM (AF) = 43.8/17.5 = 2.5 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 50 mg/kg bw/day.

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

 

NOAEL human (worker) = oral NOAEL rat * (ABSoral,rat/ ABSdermal,human)= 25 * (100%/50%) = 50 mg/kg bw/d

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

1.4

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).

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

70

 

 

1.2.3     Calculation of DNEL (dermal, worker)

DNEL= corrected NOAEL/SUM (AF) = 50/70 = 0.7 mg/kg bw/d

 

1.3     Oral (worker)

 

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

 

2      Overview derived DNEL/C´s

 

DNEC (inhalation, worker)                2.5 mg/m3 (only minor change to DNEL derivation with RA substance)

DNEL (dermal, worker)                     0.7 mg/kg bw/d (only minor change to DNEL derivation with RA substance)

DNEL (oral, worker)                          not relevant

Please note that the previously derived DNELs which were based on a RA with homologue substance were nearly the same (only marginal variation). This also indicates / underlines the connection between the both substance and shows further that the risk was adequatley controlled using the read across information.

Within the last DNEL calculationthe

NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (TNO Triskelion, 2013)

conducted with a close homolgue (2-propyn-1-ol with methyloxiran CAS 38172-91-7)

was used as the appropriate starting point for DNEL derivation.NOAEL, (f/m, systemic, oral, rats):125 mg/kg bw/d

As the active ingredient was 54.7 % this value is used for the correction of the NOAEL for RA use. Therefore we used a calculated NOAEL of 68.4 mg/kg bw/d for risk assessement.

Actual there is also information from an OECD 408 conduducted with

2-propyn-1-ol with methyloxiran CAS 38172-91-7 available. DNEL derivation based on that NOAEL may show slightly lower DNELs than derived here, but lays in the same range and underlines the assumption that the read across was conducted to the more detrimental substance and concluding hazard and risk may adequatley adressed using information form the source substance

2-propyn-1-ol with methyloxiran CAS 38172-91-7.

Nevertheless as know NOEALs are available the registred substance the calculation was done using this values.

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:
0.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
35
Modified dose descriptor starting point:
NOAEC
Value:
21.9 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:
1.4
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:
0.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
140
Modified dose descriptor starting point:
NOAEL
Value:
50 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:
1.4
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:
0.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
140
Modified dose descriptor starting point:
NOAEL
Value:
25 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:
1.4
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 2-Propyn-1-ol, polymer with ethylene oxide(CAS 25749-64-8) according to ECHA and literature.

 

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 408 study (90d study with extended investigation on reproduction parameter) (BASF 2018) was identified as the appropriate starting point for DNEL derivation.NOAEL, (f/m, systemic, oral, rats):25 mg/kg bw/d

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 21.9 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) = 68.4/4 x 70/20 = 21.9 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

1.4

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).

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

35

 

 

1.1.3     Calculation of DNEC (inhalation, general)

DNEC= corrected NOAEC/SUM (AF) = 21.9/35 = 0.6 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 50 mg/kg bw/day.

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

 

NOAEL human (worker) = oral NOAEL rat * (ABSoral,rat/ ABSdermal,human) = 25 * (100%/50%) = 50 mg/kg bw/d

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

1.4

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).

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

140

 

 

1.2.3     Calculation of DNEL (dermal, general)

DNEL= corrected NOAEL/SUM (AF) = 50/140 = 0.4 mg/kg bw/d

 

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 25 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

1.4

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).

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

140

 

 

1.3.3     Calculation of DNEL (oral, general)

DNEL=  NOAEL/SUM (AF) = 25/140 = 0.2 mg/kg bw/d

 

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)                0.6 mg/m3

Please note that the previously derived DNELs which were based on a RA with homologue substance were nearly the same (only marginal variation). This also indicates / underlines the connection between the both substance and shows further that the risk was adequatley controlled using the read across information.

Within the last DNEL calculationthe

NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (TNO Triskelion, 2013)

conducted with a close homolgue (2-propyn-1-ol with methyloxiran CAS 38172-91-7)

was used as the appropriate starting point for DNEL derivation.NOAEL, (f/m, systemic, oral, rats):125 mg/kg bw

As the active ingredient was 54.7 % this value is used for the correction of the NOAEL for RA use. Therefore we used a calculated NOAEL of 68.4 mg/kg bw for risk assessement.

Actual there is also information from an OECD 408 conduducted with

2-propyn-1-ol with methyloxiran CAS 38172-91-7 available. DNEL derivation based on that NOAEL may show slightly lower DNELs than derived here, but lays in the same range and underlines the assumption that the read across was conducted to the more detrimental substance and concluding hazard and risk may adequatley adressed using information form the source substance

2-propyn-1-ol with methyloxiran CAS 38172-91-7.

Nevertheless as know NOEALs are available the registred substance the calculation was done using this values.

DNEL (dermal, general)                    0.4 mg/kg bw/d (no change to risk assessment done with RA substance)

DNEL (oral, general)                          0.2 mg/kg bw/d (no change to risk assessment done with RA substance)

Please note that the previously derived DNELs which were based on a RA with homologue substance were nearly the same (only marginal variation). This also indicates / underlines the connection between the both substance and shows further that the risk was adequatley controlled using the read across information.

Within the last DNEL calculation the

NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (TNO Triskelion, 2013)

conducted with a close homolgue (2-propyn-1-ol with methyloxiran CAS 38172-91-7)

was used as the appropriate starting point for DNEL derivation.NOAEL, (f/m, systemic, oral, rats):125 mg/kg bw/d

As the active ingredient was 54.7 % this value is used for the correction of the NOAEL for RA use. Therefore we used a calculated NOAEL of 68.4 mg/kg bw/d for risk assessement.

Actual there is also information from an OECD 408 conduducted with

2-propyn-1-ol with methyloxiran CAS 38172-91-7 available. DNEL derivation based on that NOAEL may show slightly lower DNELs than derived here, but lays in the same range and underlines the assumption that the read across was conducted to the more detrimental substance and concluding hazard and risk may adequatley adressed using information form the source substance

2-propyn-1-ol with methyloxiran CAS 38172-91-7.

Nevertheless as know NOEALs are available the registred substance the calculation was done using this values.

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.