Alcohols, C16-18 and C18-unsatd., propoxylated

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

196 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

4.5

Modified dose descriptor starting point:

NOAEC

Value:

882 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1.5

Justification:

Batke et al., 2011

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

1

Justification:

ECETOC, Technical Report No. 110

AF for intraspecies differences:

3

Justification:

ECETOC, Technical Report No. 110

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:

1 042 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

24

Modified dose descriptor starting point:

NOAEL

Value:

25 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

2

Justification:

ECETOC, Technical Report No. 110

AF for interspecies differences (allometric scaling):

4

Justification:

Species: rat

AF for other interspecies differences:

1

Justification:

ECETOC, Technical Report No. 110

AF for intraspecies differences:

3

Justification:

ECETOC, Technical Report No. 110

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

Conversion of oral NOAEL to inhalatory NAEC

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

The conversion of an oral NOAEL (500 mg/kg bw/d; Hendy, 1982) into an inhalatory NAEC is performed using the following equation; for workers the resulting concentration needs to be additionally corrected for the difference between basal caloric demand and caloric demand under light activity:

 

Corrected inhalatory NAEC = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/wRV

                                            = oral NOAEL mg/kg bw/d x 1/0.38m³/kg bw x 1 x 6.7 m³/10 m³

sRV: standard respiratory volume, ABS: absorption, wRV: worker respiratory volume

Thus, the corrected starting point for inhalation route was 500 x 6.7 / (10 x 0.38) = 882 mg/m³

DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure etc. Molecules with a molecular weight < 500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their possibility of absorption in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to the solubilisation with bile acids and thus oral absorption may be higher than inhalation absorption. Physico-chemical and toxicokinetic parameters should be considered before using default assumptions. It is assumed that the absorption rate of AEs after oral application is almost complete (>75%, see IUCLID section 7.1). Therefore, and unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. Thus, the factor of 2 is considered to be not relevant for AE. Due to their structural similarity this assumption can also be made for alcohols propoxylated.

To extrapolate from the sub-chronic to chronic situation an assessment factor of 1.5 was applied. This assessment factor is supported by a publication of the Fraunhofer Institute for Toxicology and Experimental Medicine in cooperation with Cognis GmbH (Batke et al., 2011). Within this publication large datasets of repeated dose toxicity studies were evaluated to derive a scientifically sound assessment factor for time extrapolation, based on NOEL/C or LOEL/C ratios (short term N(L)OEL/long term N(L)OEL) for oral or inhalation administration. It was shown that an extrapolation factor of 1.5 should be used to extrapolate from the sub-chronic to the chronic situation for both, the oral and the inhalation route. Based on this newly available scientific evaluation of repeated dose toxicity studies, a time extrapolation factor of 1.5 is used. For the dermal route a factor of 2 was used as recommended by ECETOC, Technical Report No. 110

Factors applied for interspecies differences (1) and intraspecies differences (3) were applied according to ECETOC Technical Report No.110. ECETOC Assessment factors were used as these AFs are based on a critical and extensive review of the literature and represent a current state of the scientific knowledge.

Thus, the inhalatory DNEL is calculated to be 196 mg/m³.

Conversion of oral NOAEL to dermal NAEL

To convert an oral NOAEL into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for.

The dermal penetration rate for alcohol ethoxylates was calculated on the basis of a dermal penetration study with 14C-labelled C12EO6 in two human volunteers (Drotman, 1980). This penetration rate is derived from measured data and assumes - conservatively - 2% absorption within the first 24 h following dermal application.

In the study, however, the maximum systemically available C12AE6 after 144 h exposure was determined to be 1.82%. It should be noted that the study was performed only on few test subjects and that reporting was limited. However, the study clearly demonstrated that AEs penetrate poorly through human skin and clearly less readily than through rat skin. The human study was therefore judged to represent reliably the systemic availability of AEs in humans following dermal exposures to AE containing cleaning products.

It should also be noted that studies in hairless mice have shown that cutaneous absorption decreases with increasing degree of ethoxylation (EO6 to EO10) (Nishiyama et al., 1983). Thus, calculating dermal exposures to the whole range of AEs on the basis of a dermal penetration rate derived from a low ethoxylated AE such as C12AE6 can be considered as a conservative scenario. The low dermal penetration rate is also assumed for alcohols propoxlytated due to their structural similarity.

Thus, an absorption rate of 2 % after dermal application was used to correct the dermal NAEL for the differences in the absorption rate.

Corrected dermal NAEL = oral NOAEL x ABSoral-rat/ABSdermal

                                       = oral NOAEL mg/kg bw/d x 100% / 2%

ABS: absorption

Thus, the corrected starting point for dermal route was 500 x 100 / 2 = 25000 mg/kg bw/d.

DNEL derivation using the dermal NAEC

Factors applied for differences in exposure duration (2), allometric scaling (4), interspecies differences (1) and intraspecies differences (3) were applied according to ECETOC Technical Report No.110. ECETOC Assessment factors were used as these AFs are based on a critical and extensive review of the literature and represent a current state of the scientific knowledge.

Thus, the dermal DNEL is calculated to be 1042 mg/kg bw/d.

Since short-term exposure scenarios will not be assessed, only long-term DNELs for workers are derived. The oral route is not relevant for workers. In addition it is assumed that only workers will come in contact with the neat substances.

 

References:

Batke et al. 2011

M. Batke, S. Escher ,S. Hoffmann-Doerr, C. Melber ,H. Messinger, I. Mangelsdorf

Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

58 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

7.5

Modified dose descriptor starting point:

NOAEC

Value:

435 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1.5

Justification:

Batke et al., 2011

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

1

Justification:

ECETOC, Technical Report No. 110

AF for intraspecies differences:

5

Justification:

ECETOC, Technical Report No. 110

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:

625 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Value:

25 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route specific dose descriptor is not available.

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

2

Justification:

ECETOC, Technical Report No. 110

AF for interspecies differences (allometric scaling):

4

Justification:

Species: rat

AF for other interspecies differences:

1

Justification:

ECETOC, Technical Report No. 110

AF for intraspecies differences:

5

Justification:

ECETOC, Technical Report No. 110

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:

17 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: Guidance on Assessment Factors to Derive a DNEL (ECETOC, Technical Report No. 110)

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:

1

Justification:

NOAEL is chosen as starting point.

AF for differences in duration of exposure:

1.5

Justification:

Batke et al., 2011

AF for interspecies differences (allometric scaling):

4

Justification:

Species: rat

AF for other interspecies differences:

1

Justification:

ECETOC, Technical Report No. 110

AF for intraspecies differences:

5

Justification:

ECETOC, Technical Report No. 110

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

Conversion of oral NOAEL to inhalatory NAEC

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a correct starting point by route-to-route extrapolation based on the ECHA guidance document "Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health", November 2012.

The conversion of an oral NOAEL(500 mg/kg bw/d; Hendy, 1982) into an inhalatory NAEC is performed using the following equation:

Corrected inhalatory NAEC = oral NOAEL x 1/sRVrat x ABSoral-rat/ABSinh-human

                                            = oral NOAELmg/kg bw/dx 1/1.15 m³/kg bw x 1

sRV: standard respiratory volume, ABS: absorption

Thus, the corrected starting point for inhalation route was 500 x 1 / 1.15 = 435 mg/m³

DNEL derivation using the inhalatory NAEC

In the ECHA Guidance a factor of 2 is suggested for the extrapolation from oral to inhalation absorption. On the contrary, the Technical guidance document on risk assessment in support of Commission directive 93/67/EEC, 2003 appendix IV A and B gives a number of physico-chemical properties that normally determine oral, inhalation and dermal absorption. These parameters include molecular weight, log Kow, pKa values and for inhalation also particle size distribution, vapour pressure etc. Molecules with a molecular weight < 500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their possibility of absorption in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to the solubilisation with bile acids and thus oral absorption may be higher than inhalation absorption. Physico-chemical and toxicokinetic parameters should be considered before using default assumptions. It is assumed that the absorption rate of AEs after oral application is almost complete (>75%, see IUCLID section 7.1). Therefore, and unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route. Thus, the factor of 2 is considered to be not relevant for AEs.  Due to their structural similarity this assumption can also be made for alcohols propoxylated.

To extrapolate from the sub-chronic to chronic toxicity an assessment factor of 1.5 was applied. This assessment factor is supported by a publication of the Fraunhofer Institute for Toxicology and Experimental Medicine in cooperation with Cognis GmbH (Batke et al., 2011). Within this publication large datasets of repeated dose toxicity studies were evaluated to derive a scientifically sound assessment factor for time extrapolation, based on NOEL/C or LOEL/C ratios (short term N(L)OEL/long term N(L)OEL) for oral or inhalation administration. It was shown that an extrapolation factor of 1.5 should be used to extrapolate from the sub-chronic to the chronic situation for both, the oral and the inhalation route. Based on this newly available scientific evaluation of repeated dose toxicity studies a time extrapolation factor of 1.5 is used. For the dermal route a factor of 2 was used as recommended by ECETOC, Technical Report No. 110

Factors applied for interspecies differences (1) and intraspecies differences (5) were applied according to ECETOC Technical Report No.110. ECETOC Assessment factors were used as these AFs are based on a critical and extensive review of the literature and represent a current state of the scientific knowledge.

Thus, the inhalatory DNEL is calculated to be 58 mg/m³.

Conversion of oral NOAEL to dermal NAEL

To convert an oral NOAEL into a dermal NAEL, the differences in absorption between routes as well as differences in dermal absorption between rats and humans have to be accounted for.

The dermal penetration rate for alcohol ethoxylates was calculated on the basis of a dermal penetration study with 14C-labelled C12EO6 in two human volunteers (Drotman, 1980). This penetration rate is derived from measured data and assumes - conservatively - 2% absorption within the first 24 h following dermal application.

In the study, however, the maximum systemically available C12AE6 after 144 h exposure was determined to be 1.82%. It should be noted that the study was performed only on few test subjects and that reporting was limited. However, the study clearly demonstrated that AEs penetrate poorly through human skin and clearly less readily than through rat skin. The human study was therefore judged to represent more reliably the systemic availability of AEs in humans following dermal exposures to AE containing cleaning products. It should also be noted that studies in hairless mice have shown that cutaneous absorption decreases with increasing degree of ethoxylation (EO6 to EO10) (Nishiyama et al., 1983). Thus, calculating dermal exposures to the whole range of AEs on the basis of a dermal penetration rate derived from a low ethoxylated AE such as C12AE6 can be considered as a conservative scenario. The low dermal penetration rate is also assumed for alcohols propoxylated due to their structural similarity.

Thus, an absorption rate of 2 % after dermal application was used to correct the dermal NAEL for the differences in the absorption rate.

Corrected dermal NAEL = oral NOAEL x ABSoral-rat/ABSdermal

                                       = oral NOAELmg/kg bw/d x100% / 2%

ABS: absorption

Thus, the corrected starting point for dermal route was 500 x 100 / 2 = 25000 mg/kg bw/d.

DNEL derivation using the dermal NAEC

Factors applied for differences in exposure duration (2), allometric scaling (4), interspecies differences (1) and intraspecies differences (5) were applied according to ECETOC Technical Report No.110. ECETOC Assessment factors were used as these AFs are based on a critical and extensive review of the literature and represent a current state of the scientific knowledge.

Thus, the dermal DNEL is calculated to be 625 mg/kg bw/d.

Since short-term exposure scenarios will not be assessed, only long-term DNELs for general population are derived.

DNEL derivation for oral route

To extrapolate from the sub-chronic to chronic toxicity an assessment factor of 1.5 was applied. This assessment factor is supported by a publication of the Fraunhofer Institute for Toxicology and Experimental Medicine in cooperation with Cognis GmbH (Batke et al., 2011). Within this publication large datasets of repeated dose toxicity studies were evaluated to derive a scientifically sound assessment factor for time extrapolation, based on NOEL/C or LOEL/C ratios (short term N(L)OEL/long term N(L)OEL) for oral or inhalation administration. It was shown that an extrapolation factor of 1.5 should be used to extrapolate from the sub-chronic to the chronic situation for both, the oral and the inhalation route. Based on this newly available scientific evaluation of repeated dose toxicity studies a time extrapolation factor of 1.5 is used.

Factors applied for allometric scaling (4), interspecies differences (1) and intraspecies differences (5) were applied according to ECETOC Technical Report No.110. ECETOC Assessment factors were used as these AFs are based on a critical and extensive review of the literature and represent a current state of the scientific knowledge.

Thus, the oral DNEL is calculated to be 17 mg/kg bw/d.

 

References:

Batke et al. 2011

M. Batke, S. Escher ,S. Hoffmann-Doerr, C. Melber ,H. Messinger, I. Mangelsdorf

Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129