α,α'-propylenedinitrilodi-o-cresol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.11 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

42.5

Modified dose descriptor starting point:

NOAEC

Value:

132.23 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (WIL Reseach Europe, 2013) was identified

as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day). 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 132.23 mg/m³.

AF for dose response relationship:

1

Justification:

See discussion section

AF for differences in duration of exposure:

3.4

Justification:

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.

AF for interspecies differences (allometric scaling):

1

Justification:

See discussion section

AF for other interspecies differences:

1

Justification:

See discussion section

AF for intraspecies differences:

5

Justification:

Recommended in REACh Guidance document R.8 

AF for the quality of the whole database:

1

Justification:

See discussion section

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8 

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:

0.88 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

170

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (WIL Reseach Europe, 2013) was identified as the

appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day). This 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 based on the available data which resulted in a corrected starting point for DNEL derivation for worker of 150 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

See discussion section

AF for differences in duration of exposure:

3.4

Justification:

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.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

See discussion section

AF for intraspecies differences:

5

Justification:

Recommended in REACh Guidance document R.8 

AF for the quality of the whole database:

1

Justification:

See discussion section

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8 

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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Worker:

Based on the available data alpha,alpha'-propylenedinitrilodi-o-cresol, has to be considered as harmful if swallowed Cat. 4 according to EC/1271/2008, potentially skin sensitizing (Cat. 1) and toxic to reproduction (Cat. 1B Fertility and Development), respectively.

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).

Dermal short-term exposure – local effects:

For the sensitization potential, a qualitative assessment was conducted:

Though sensitization reactions of the skin are generally regarded as threshold effect, deriving a threshold and setting a DNEL is very difficult in practice. No dose-response data of the tested substance are on-hand, which would a support quantitative determination of a DNEL.

Based on the available old data with epicutaneous open induction at 20 % and a challenge concentration of 2 % (epicutaneous, open), the test substance is a moderate to strong skin sensitizer.

Therefore the use of gloves is required in order to prevent any skin contact with the test substance and thus the occurrence of skin sensitization.

Inhalation 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) (WIL Reseach Europe, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day).

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 132.23 mg/m³.

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

-         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 = 2.5 x 5 x 3.4 x 1 = 42.5

Based on this calculation the resulting DNEL is 3.11 mg/m³.

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) (WIL Reseach Europe, 2013) was identified as the appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day).

This 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 based on the available data which resulted in a corrected starting point for DNEL derivation for worker of 150 mg/kg bw/day.

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: 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 0.88 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:

0.76 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

85

Modified dose descriptor starting point:

NOAEC

Value:

65.21 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (WIL Reseach Europe, 2013) was identified as the

appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day). 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 65.21 mg/m³.

AF for dose response relationship:

1

Justification:

See discussion section

AF for differences in duration of exposure:

3.4

Justification:

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.

AF for interspecies differences (allometric scaling):

1

Justification:

See discussion section

AF for other interspecies differences:

1

Justification:

See discussion section

AF for intraspecies differences:

10

Justification:

Recommended in REACh Guidance document R.8

AF for the quality of the whole database:

1

Justification:

See discussion section

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8

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:

0.44 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

340

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (WIL Reseach Europe, 2013) was identified as the

appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day). This 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 based on the available data which resulted in a corrected starting point for DNEL derivation for worker of 150 mg/kg bw/day.

AF for dose response relationship:

1

Justification:

See discussion section

AF for differences in duration of exposure:

3.4

Justification:

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).

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

See discussion section

AF for intraspecies differences:

10

Justification:

Recommended in REACh Guidance document R.8 

AF for the quality of the whole database:

1

Justification:

See discussion section

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8 

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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.22 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

340

Modified dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (WIL Reseach Europe, 2013) was identified as the

appropriate starting point for DNEL derivation for long-term oral exposure. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day).

AF for dose response relationship:

1

Justification:

See discussion section

AF for differences in duration of exposure:

3.4

Justification:

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).

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

See discussion section

AF for intraspecies differences:

10

Justification:

Recommended in REACh Guidance document R.8

AF for the quality of the whole database:

1

Justification:

See discussion section

AF for remaining uncertainties:

2.5

Justification:

Recommended in REACh Guidance document R.8

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

Consumer

Based on the available data alpha,alpha'-propylenedinitrilodi-o-cresol, has to be considered as harmfull if swallowed (Cat. 4 according to EC/1271/2008), potentially skin sensitizing (Cat. 1) and toxic to reproduction (Cat. 1B Fertility and Development), respectively.

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

Dermal short-term exposure – local effects:

For the sensitization potential, a qualitative assessment was conducted:

Though sensitization reactions of the skin are generally regarded as threshold effect, deriving a threshold and setting a DNEL is very difficult in practice. No dose-response data of the tested substance are on-hand, which would a support quantitative determination of a DNEL.

Based on the available old data with epicutaneous open induction at 20 % and a challenge concentration of 2 % (epicutaneous, open), the test substance is a moderate to strong skin sensitizer.

Therefore the use of gloves might be required depending on the substance concentration the consumer is exposed to in products and articles.

Inhalation 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) (WIL Reseach Europe, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day).

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 65.21 mg/m³.

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

-         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). 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 = 2.5 x 10 x 3.4 x 1 = 85

Based on this calculation the resulting DNEL is 0.76 mg/m³.

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) (WIL Reseach Europe, 2013) was identified as the appropriate starting point for DNEL derivation for long-term dermal exposure. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day).

This 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 based on the available data which resulted in a corrected starting point for DNEL derivation for worker of 150 mg/kg bw/day.

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: interspecies differences (4), remaining differences (1), intraspecies differences (5), exposure duration (3.4) (AF = 4 x 2.5 x 10 x 3.4 x 1 x 1 = 340).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 0.44 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

-         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

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.

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) (WIL Reseach Europe, 2013) was identified as the appropriate starting point for DNEL derivation for long-term oral exposure. The NOAEL for reproduction and development of the test substance was 75 mg/kg bw/day (NOAEL systemic was at 250 mg/kg bw/day).

The NOAEL of 75 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 (5), exposure duration (3.4) (AF = 4 x 2.5 x 10 x 3.4 x 1 x 1 = 340).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 0.22 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

-         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

- 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.