Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
146.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
Value:
881.5 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point). This is in line with the ECHA R8 guidance document.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.
AF for other interspecies differences:
1
Justification:
Based on the absence of evident systemic/ organ specific toxicity up to and including the limit dose, an additional AF for interspecies differences other than allometric scaling is not considered necessary.
AF for intraspecies differences:
3
Justification:
Substance specific assessment factor: No relevant adverse systemic effects were observed up to and including the limit dose of 1000 mg/kg bw/d. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 3 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be adequate for a robust DNEL derivation.
AF for remaining uncertainties:
1
Justification:
Substance specific assessment factor: Subchronic administration of the test item resulted in no adverse effects up to and including the limit dose. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.   
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:
41.66 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default value for extrapolation from subchronic to chronic exposure is used in order to cover the exposure duration (90 days).
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used (ECHA R8, 2012).
AF for other interspecies differences:
1
Justification:
Based on the absence of evident systemic/ organ specific toxicity up to and including the limit dose, an additional AF for interspecies differences other than allometric scaling is not considered necessary.
AF for intraspecies differences:
3
Justification:
Substance specific assessment factor: No relevant adverse systemic effects were observed up to and including the limit dose of 1000 mg/kg bw/d. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 3 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be adequate for a robust DNEL derivation.
AF for remaining uncertainties:
1
Justification:
Substance specific assessment factor: Subchronic administration of the test item resulted in no adverse effects up to and including the limit dose. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.   
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Short-term exposure - systemic and local effects

Dexpanthenol did not cause any deaths, clinical signs or adverse effects during an inhalation risk test. Since it is a viscous substance of very low vapour pressure, the exposure to Dexpanthenol vapour is very unlikely. Furthermore, Dexpanthenol and its structural analoga DL-Panthenol and Ethylpanthenol (for read across justification please refer to chapter 13) did not induce any relevant systemic adverse effects in acute (oral, dermal, inhalation) and repeated dose studies (oral) and did not cause skin sensitization or irritation to skin and eyes. As the test item did neither show acute systemic nor acute local toxicity, the derivation of acute DNELs for systemic and local effects is not considered mandatory.

Long-term exposure - systemic effects

For Dexpanthenol or its structural analoga DL-Panthenol and Ethylpanthenol(for read across justification please refer to chapter 13) several repeated dose studies are available. In an oral (gavage) 28 days subacute study (OECD 407) and an oral (gavage) 90 days subchronic study (OECD 408) in rats there were no adverse effects observed up to the limit dose of 1000 mg/kg bw/d. In an reproduction/developmental toxicity screening study (similar to OECD 412) as well as a prenatal developmental toxicity study (OECD 414) in rats no adverse effects occurred in parental animals or pups up to the limit dose of 1000 mg/kg bw/d. In the absence of a suitable inhalation and dermal toxicity study with repeated exposure, the worker-DNELs long-term for inhalation and dermal route - systemic were derived from the NOAEL obtained in the oral 90 days repeated dose study in rats (WIL 2012) conducted with Ethylpanthenol which is a structural analogon of Dexpanthenol (for read across justification please refer to chapter 13).

Inhalation exposure

A corrected inhalatory NOAEC (NOAECcorr) was calculated using the default respiratory volume for the rat and a correction for the difference between human respiratory rates under standard conditions and under conditions of light activity. As specified by ECHA (2012) a two times higher inhalation absorption rate compared to oral absorption was assumed.

 

Calculation of the NOAECcorr

- Standard dose descriptor (NOAEL): 1000 mg/kg bw/d

- Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d

- Oral absorption of the rat/inhalation absorption of humans (ABSoral-rat)/ABSinhal-human): 50/100

- Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

- Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Corrected inhalatory NOAEC for workers:

= NOAEL * (1/sRVrat) * (ABSoral-rat/ABSinhal-human) *(sRVhuman/wRV)

= 1000 mg/kg bw/d * (1/0.38 m³/kg bw/d)* (50/100) * (6.7 m³/10 m³)

= 881.5 mg/m³

According to ECHA R8 (2012) the following default assessment factors were applied:

exposure duration: 2 (subchronic to chronic)

quality of whole data base: 1 (based on the validity of the well performed OECD guidline studies)

dose response: 1

The following substance specific assessment factors (AF) were applied:

intraspecies differences : 3

remaining differences: 1

Calculation of the worker DNEL for long-term inhalation exposure:

DNEL = NOAECcorr/ AF = 881.5 mg/m³ / (2 * 1 * 1 * 3 * 1) = 146.9 mg/m³

Dermal exposure

Route to route extrapolation: oral – dermal:

Since quantitative data for the skin penetration potential of Dexpathenol are not available, a default value of 50% is chosen for percutaneous penetration and absorption in humans as well as oral bioavailability in rats according to ECHA R8 (2012). The basis for the calculation of the DNEL for systemic effects of dermal long-term exposure is the NOAEL of 1000 mg/kg bw/d derived from the oral (gavage) 90 days subchronic repeated dose toxicity study in rats (WIL 2012).

 

The oral NOAEL was converted into a corrected dermal NOAEL according to the procedure, recommended in the current guidance document (R8, ECHA 2012).

 

NOAELcorr dermal = 1000 mg/kg bw/d *(50/50) = 1000 mg/kg bw/d

According to ECHA R8 (2012) the following default assessment factors were applied:

exposure duration: 2 (subchronic to chronic)

quality of whole data base: 1 (based on the validity of the well performed OECD guidline studies)

dose response: 1

allometric scaling: 4 (rat to human)

The following substance specific assessment factors (AF) were applied:

intraspecies differences : 3

remaining differences: 1

Calculation of the worker DNEL for long-term dermal exposure:

DNEL = NOAELcorr/ AF = 1000 mg/kg bw/d / (2 * 1 * 1 * 4 * 3 * 1) = 41.6 mg/kg bw/d

Derivation from the standard AF for intraspecies differences and remaining differences:

For Dexpanthenol or its structural analoga DL-Panthenol and Ethylpanthenol(for read across justification please refer to chapter 13) several repeated dose studies are available. In an oral (gavage) 28 days subacute study (OECD 407) and an oral (gavage) 90 days subchronic study (OECD 408) in rats there were no adverse effects observed up to and including the limit dose of 1000 mg/kg bw/d. In an reproduction/ developmental toxicity screening study (similar to OECD 412) as well as a prenatal developmental toxicity study (OECD 414) in rats no adverse effects occurred in parental animals or pups up to and including the limit dose of 1000 mg/kg bw/d. In conclusion, oral exposure did not cause any adverse systemic effects in rats and no human relevant organ specific toxicity up to and including the limit dose of 1000 mg/kg bw/day. Thus, no additional AF covering remaining differences is considered to be neccessary. Furthermore, there were no effects observed which are supposed to be dependent on human intraspecies variations in toxicokinetics or toxicodynamics. Although an additional AF for intraspecies differences would not be required, an AF of 3 has been included to cover potential variations within a controlled subpopulation, i.e. healthy workers.

Long-term exposure – local effects

The test item did not induce any local toxic effects. There was no evidence of toxicity in any of the available studies. Thus, the derivation of a long-term DNEL for local effects is not required. This is in line with the ECHA guidance document (2012).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43.47 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
Value:
434.78 mg/m³
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point). This is in line with the ECHA R8 guidance document.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is not applied, because the ventilation rate directly depends on the basal metabolic rate.
AF for other interspecies differences:
1
Justification:
Based on the absence of evident systemic/ organ specific toxicity up to and including the limit dose, an additional AF for interspecies differences other than allometric scaling is not considered necessary.
AF for intraspecies differences:
5
Justification:
Substance specific assessment factor: No relevant adverse systemic effects were observed up to and including the limit dose of 1000 mg/kg bw/d. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be adequate for a robust DNEL derivation.
AF for remaining uncertainties:
1
Justification:
Substance specific assessment factor: Subchronic administration of the test item resulted in no adverse effects up to and including the limit dose. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.   
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:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point). This is in line with the ECHA R8 guidance document.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used (ECHA R8, 2012).
AF for other interspecies differences:
1
Justification:
Based on the absence of evident systemic/ organ specific toxicity up to and including the limit dose, an additional AF for interspecies differences other than allometric scaling is not considered necessary.
AF for intraspecies differences:
5
Justification:
Substance specific assessment factor: No relevant adverse systemic effects were observed up to and including the limit dose of 1000 mg/kg bw/d. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be adequate for a robust DNEL derivation.
AF for remaining uncertainties:
1
Justification:
Substance specific assessment factor: Subchronic administration of the test item resulted in no adverse effects up to and including the limit dose. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.   
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
40
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point). This is in line with the ECHA R8 guidance document.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used (ECHA R8, 2012).
AF for other interspecies differences:
1
Justification:
Based on the absence of evident systemic/ organ specific toxicity up to and including the limit dose, an additional AF for interspecies differences other than allometric scaling is not considered necessary.
AF for intraspecies differences:
5
Justification:
Substance specific assessment factor: No relevant adverse systemic effects were observed up to and including the limit dose of 1000 mg/kg bw/d. Due to the absence of such effects, intraspecies variations in toxicokinetics or toxicodynamics are not considered relevant. However an AF of 5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment. Additional generic argumentation: In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be adequate for a robust DNEL derivation.
AF for remaining uncertainties:
1
Justification:
Substance specific assessment factor: Subchronic administration of the test item resulted in no adverse effects up to and including the limit dose. Since no human relevant organ specific toxicity has been observed, no additional AF covering toxicodynamic differences between rats and humans is considered necessary.   
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

Short-term exposure - systemic and local effects

Dexpanthenol did not cause any deaths, clinical signs or adverse effects during an inhalation risk test. Since it is a viscous substance of very low vapour pressure, the exposure to Dexpanthenol vapour is very unlikely. Furthermore, Dexpanthenol and its structural analoga DL-Panthenol and Ethylpanthenol (for read across justification please refer to chapter 13) did not induce any relevant systemic adverse effects in acute (oral, dermal, inhalation) and repeated dose studies (oral) and did not cause skin sensitization or irritation to skin and eyes. As the test item did neither show acute systemic nor acute local toxicity, the derivation of acute DNELs for systemic and local effects is not considered mandatory.

Long-term exposure - systemic effects

For Dexpanthenol or itsstructural analoga DL-Panthenol and Ethylpanthenol(for read across justification please refer to chapter 13) several repeated dose studies are available. In an oral (gavage) 28 days subacute study (OECD 407) and an oral (gavage) 90 days subchronic study (OECD 408) in rats there were no adverse effects observed up to the limit dose of 1000 mg/kg bw/d. In an reproduction/developmental toxicity screening study (similar to OECD 412) as well as a prenatal developmental toxicity study (OECD 414) in rats no adverse effects occurred in parental animals or pups up to the limit dose of 1000 mg/kg bw/d. In the absence of a suitable inhalation and dermal toxicity study with repeated exposure, the DNELs long-term for inhalation and dermal route - systemic were derived from the NOAEL obtained in the oral 90 days repeated dose study in rats (WIL 2012) conducted with Ethylpanthenol which is a structural analogon of Dexpanthenol (for read across justification please refer to chapter 13).

Inhalation exposure

A corrected inhalatory NOAEC (NOAECcorr) was calculated using the default respiratory volume for rat and humans. As specified by ECHA (2012) a two times higher inhalation absorption rate compared to oral absorption was assumed.

 

Calculation of the NOAECcorr

- Standard dose descriptor (NOAEL): 1000 mg/kg bw/d

- Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw/d

- Oral absorption of the rat/inhalation absorption of humans (ABSoral-rat)/ABSinhal-human): 50/100

Corrected inhalatory NOAEC for the general population:

= NOAEL * (1/sRVrat) * (ABSoral-rat/ABSinhal-human)

= 1000 mg/kg bw/d * (1/1.15 m³/kg bw/d)* (50/100)

= 434.78 mg/m³

According to ECHA R8 (2012) the following default assessment factors were applied:

exposure duration: 2 (subchronic to chronic)

quality of whole data base: 1 (based on the validity of the well performed OECD guidline studies)

dose response: 1

The following substance specific assessment factors (AF) were applied:

intraspecies differences : 5

remaining differences: 1

Calculation of the general population DNEL for long-term inhalation exposure:

DNEL = NOAECcorr/ AF = 434.78 mg/m³ / (2 * 1 * 1 * 5 * 1) = 43.47 mg/m³

Dermal exposure

Route to route extrapolation: oral – dermal:

Since quantitative data for the skin penetration potential of Dexpathenol are not available, a default value of 50% is chosen for percutaneous penetration and absorption in humans as well as oral bioavailability in rats according to ECHA R8 (2012). The basis for the calculation of the DNEL for systemic effects of dermal long-term exposure is the NOAEL of 1000 mg/kg bw/d derived from the oral (gavage) 90 days subchronic repeated dose toxicity study in rats (WIL 2012).

 

The oral NOAEL was converted into a corrected dermal NOAEL according to the procedure, recommended in the current guidance document (R8, ECHA 2012).

 

NOAELcorr dermal = 1000 mg/kg bw/d *(50/50) = 1000 mg/kg bw/d

According to ECHA R8 (2012) the following default assessment factors were applied:

exposure duration: 2 (subchronic to chronic)

quality of whole data base: 1 (based on the validity of the well performed OECD guidline studies)

dose response: 1

allometric scaling: 4 (rat to human)

The following substance specific assessment factors (AF) were applied:

intraspecies differences : 5

remaining differences: 1

Calculation of the general population DNEL for long-term dermal exposure:

DNEL = NOAELcorr/ AF = 1000 mg/kg bw/d / (2 * 1 * 1 * 4 * 5 * 1) = 25 mg/kg bw/d

Oral exposure

The basis for the calculation of the DNEL for systemic effects of oral long-term exposure is the NOAEL of 1000 mg/kg bw/d derived from the oral (gavage) 90 days subchronic repeated dose toxicity study in rats (WIL 2012).

 

According to ECHA R8 (2012) the following default assessment factors were applied:

exposure duration: 2 (subchronic to chronic)

quality of whole data base: 1 (based on the validity of the well performed OECD guidline studies)

dose response: 1

allometric scaling: 4 (rat to human)

The following substance specific assessment factors (AF) were applied:

intraspecies differences : 5

remaining differences: 1

Calculation of the general population DNEL for long-term oral exposure:

DNEL = NOAEL / AF = 1000 mg/kg bw/d / (2 * 1 * 1 * 4 * 5 * 1) = 25 mg/kg bw/d

Derivation from the standard AF for intraspecies differences and remaining differences:

For Dexpanthenol or itsstructural analoga DL-Panthenol and Ethylpanthenol(for read across justification please refer to chapter 13) several repeated dose studies are available. In an oral (gavage) 28 days subacute study (OECD 407) and an oral (gavage) 90 days subchronic study (OECD 408) in rats there were no adverse effects observed up to and including the limit dose of 1000 mg/kg bw/d. In an reproduction/ developmental toxicity screening study (similar to OECD 412) as well as a prenatal developmental toxicity study (OECD 414) in rats no adverse effects occurred in parental animals or pups up to and including the limit dose of 1000 mg/kg bw/d. In conclusion, oral exposure did not cause any adverse systemic effects in rats and no human relevant organ specific toxicity up to and including the limit dose of 1000 mg/kg bw/day. Thus, no additional AF covering remaining differences is considered to be neccessary. Furthermore, there were no effects observed which are supposed to be dependent on human intraspecies variations in toxicokinetics or toxicodynamics. Although an additional AF for intraspecies differences would not be required, an AF of 5 has been included to cover potential variations in the general population.

Long-term exposure – local effects

The test item did not induce any local toxic effects. There was no evidence of toxicity in any of the available studies. Thus, the derivation of a long-term DNEL for local effects is not required. This is in line with the ECHA guidance document (2012).