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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
285 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):
3
Modified dose descriptor starting point:
NOAEC
DNEL value:
860 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
Justification:
sub-chronic and chronic studies in rats resulted in an equal NOAEL (Munday et al., 1995a,b).
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
1
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
AF for intraspecies differences:
3
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 060 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):
12
Modified dose descriptor starting point:
NOAEL
DNEL value:
48 800 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Adequate 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
Justification:
sub-chronic and chronic studies in rats resulted in an equal NOAEL (Munday et al., 1995a,b).
AF for interspecies differences (allometric scaling):
4
Justification:
Species: rat
AF for other interspecies differences:
1
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
AF for intraspecies differences:
3
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The alkyl sulfates of the category comprise carbon chain length of C8 to C18 and are grouped together due to their structural similarities and comparable physicochemical, toxicological and ecotoxicological properties. The possibility of a read-across between diferent alkyl sulfates is in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. Grouping of substances. In Annex XI 1.5 it is given that a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The AS reported within the AS category show structural similarity. The alkyl chain length in the alkyl sulfate category varies from C8 to C18. In addition most chemicals of this category are not defined substances, but mixtures of homologues with different alkyl chain lengths (UVCBs). The most important common structural feature of the category members is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate group, neutralized with a counter ion. This structural feature confers the surfactant properties of the alkyl sulfates. The surfactant property of the members of the AS category in turn represent the predominant attribute in mediating effects on mammalian health. Due to the structural similarities also the disposition within the body is comparable throughout the category. The AS of the AS category also have similar physico-chemical, environmental and toxicological properties, validating the read across approach within the category. The approach of grouping different AS for the evaluation of their toxicokinetics, metabolism and distribution as well as their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]). A detailed justification for grouping of alkyl sulfates into a category is provided separately. Please refer for more details on the read-across also to the document “AS Category Approach Justification” attached in section 13 of IUCLID.

Since there is no dose descriptor for every route of exposure, 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", Nov 2012.

The NOAELs and LOAELs achieved within the different studies draw a coherent picture and the subchronic and chronic LOAELs are in the same range and the subchronic NOAELs do not conflict with the chronic LOAEL, Therefore the dietary NOAEL of 488 mg/kg bw/day (Munday et al., 1976a) representing an average of the NOAELs, was chosen as starting point. For details on study selection please refer to the endpoint summary in IUCLID section 7.5: Repeated dose toxicity.

In general an AF of 2 is applied when extrapolating data of subchronic toxicity studies to the chronic situation. However, as discussed above repeated dose toxicity data revealed comparable NOELs/NOAELs after subchronic and chronic treatment. Based on this fact there is no uncertainty regarding the extrapolation from subchronic to chronic exposure and thus a factor of 1 is applied for exposure duration.

 

Conversion of oral NOAEL to inhalatory NAEC

The conversion of an oral NOAEL into an inhalatory NAEC is performed using the following equations; 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 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 488 *6.7 / (10 x 0.38) = 860 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 KOWbetween 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 toxikokinetic parameters should be considered before using default assumptions. Absorption via the oral route is complete (100%, see section IUCLID 7.1 Toxicokinetics) therefore equal absorption can be assumed when extrapolating from oral to inhalation route.

There is evidence that association between intra- and inter-species assessment factors is conservative and that the inclusion of a remaining difference factor is unnecessary. ECETOC (2003) analyzed the available data of Freireich et al. (1966), Schein et al. (1979), and Watanabe et al. (1992) and concluded that apart from allometric scaling there is the likelihood of additional variability around the extrapolated dose or predicted NOAEL in humans. However, this additional variability is probably due not only to possible differences in biological sensitivity between species, but also to intraspecies differences. Apart from these aspects, one also has to consider the different endpoints (maximum tolerated dose – MTD - versus toxic dose low - TDL) used for the evaluation of human and animal data. Thus, it is evident that the comparison of ‘toxic doses’ across species is actually a comparison between doses that cause ‘dose-limiting’ toxicity (MTDH) in a sensitive subpopulation of humans (health-compromised, cancer patients) at one extreme and lethality in 10% of the population of otherwise assumed healthy animals (lethal dose - LD10) at the other. This will overestimate the sensitivity of humans in relation to other species, but to an extent which is unquantifiable.

This uncertainty is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). This assumption is further supported by a publication of the Fraunhofer Institute for Toxicology and Experimental Medicine in cooperation with BASF Personal Care and Nutrition GmbH. Within this publication large datasets of repeated dose toxicity studies were evaluated to derive a scientifically sound assessment factor for interspecies extrapolation. It was shown that, despite the factor for allometric scaling, no additional factor for interspecies differences is required (Escher et al. 2013). Based on this newly available scientific evaluation of repeated dose toxicity studies an interspecies factor of 1 is used. For the total (inter- and intraspecies) variability, ECETOC proposed an overall factor of 3 for the workplace and of 5 for the general population which were consequently used for DNEL derivation.

The inhalatory DNEL is calculated to be 285 mg/m3.

 

Conversion of oral NOAEL to dermal NAEL for systemic toxicity

The study investigating the dermal route resulted in significant local irritation. It provided some evidence of systemic toxicity however this response could be associated with the significant dermal inflammation. Thus, the NOAEL used for the risk assessment was based on a dietary study to assess potential systemic toxicity resulting from repeated exposures to AS.

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 absorption of AS is relatively poor as can be expected from an anionic molecule which tends to bind to the skin surface (HERA, 2002; Howes, 1975; Black & Howes, 1980). Experimental animal data with14C-labelled C12AS Na in guinea pigs showed that 0.35% of the applied dose of 3 µmol was absorbed (Prottey & Ferguson, 1975). Therefore including a default assumption of 1% for all modelled exposures will display a sufficient conservative approach.

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

                                       = oral NOAEL x 100/1

ABS: absorption

The corrected dermal dose descriptor is calculated to be 48800 mg/kg bw/d.

 

DNEL derivation using the dermal NAEC

There is evidence that association between intra- and inter-species assessment factors is conservative and that the inclusion of a remaining difference factor is unnecessary. ECETOC (2003) analyzed the available data of Freireich et al. (1966), Schein et al. (1979), and Watanabe et al. (1992) and concluded that apart from allometric scaling there is the likelihood of additional variability around the extrapolated dose or predicted NOAEL in humans. However, this additional variability is probably due not only to possible differences in biological sensitivity between species, but also to intraspecies differences. Apart from these aspects, one also has to consider the different endpoints (maximum tolerated dose – MTD - versus toxic dose low - TDL) used for the evaluation of human and animal data. Thus, it is evident that the comparison of ‘toxic doses’ across species is actually a comparison between doses that cause ‘dose-limiting’ toxicity (MTDH) in a sensitive subpopulation of humans (health-compromised, cancer patients) at one extreme and lethality in 10% of the population of otherwise assumed healthy animals (lethal dose - LD10) at the other. This will overestimate the sensitivity of humans in relation to other species, but to an extent which is unquantifiable.

This uncertainty is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). This assumption is further supported by a publication of the Fraunhofer Institute for Toxicology and Experimental Medicine in cooperation with BASF Personal Care and Nutrition GmbH. Within this publication large datasets of repeated dose toxicity studies were evaluated to derive a scientifically sound assessment factor for interspecies extrapolation. It was shown that, despite the factor for allometric scaling, no additional factor for interspecies differences is required (Escher et al. 2013). Based on this newly available scientific evaluation of repeated dose toxicity studies an interspecies factor of 1 is used. For the total (inter- and intraspecies) variability, ECETOC proposed an overall factor of 3 for the workplace and of 5 for the general population which were consequently used for DNEL derivation.

The dermal systemic DNEL is calculated to be 4060 mg/kg bw/d.

 

In addition it is assumed that only workers will come in contact with the neat substances. Due to the known irritating potential of undiluted AS it is common to use personal protective equipment like gloves to avoid dermal contact therewith considering local DNELs as obsolete.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
85 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):
5
Modified dose descriptor starting point:
NOAEC
DNEL value:
424 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
Justification:
sub-chronic and chronic studies in rats resulted in an equal NOAEL (Munday et al., 1995a,b).
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route.
AF for other interspecies differences:
1
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
AF for intraspecies differences:
5
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 440 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):
20
Modified dose descriptor starting point:
NOAEL
DNEL value:
48 800 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Adequate 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
Justification:
sub-chronic and chronic studies in rats resulted in an equal NOAEL (Munday et al., 1995a,b).
AF for interspecies differences (allometric scaling):
4
Justification:
Species: rat
AF for other interspecies differences:
1
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
AF for intraspecies differences:
5
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24 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):
20
Modified dose descriptor starting point:
NOAEL
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
Justification:
sub-chronic and chronic studies in rats resulted in an equal NOAEL (Munday et al., 1995a,b).
AF for interspecies differences (allometric scaling):
4
Justification:
Species: rat
AF for other interspecies differences:
1
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
AF for intraspecies differences:
5
Justification:
Factor for alkyl sulfates based on ECETOC, Technical Report No. 110. Please refer to the discussion.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

For more details on the chosen starting point, Assessment Factors and Read-Across, please refer to the discussion for workers. 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", Nov 2012.

The conversion of an oral NOAEL into an inhalatory NAEC is performed using the following equations:

 

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

                                            = oral NOAEL x 1/1.15 m³/kg bw x 1

 

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

 

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 KOWbetween 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. The consideration of physico-chemical parameters should be performed before using default assumptions. 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. Absorption via the oral route is complete (100%, see section IUCLID 7.1 Toxicokinetics) therefore equal absorption can be assumed when extrapolating from oral to inhalation route.

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 absorption of AS is relatively poor as can be expected from an anionic molecule which tends to bind to the skin surface (HERA, 2002; Howes, 1975; Black & Howes, 1980). Experimental animal data with 14C-labelled C12 ASO4 Na in guinea pigs showed that 0.35% of the applied dose of 3 µmol was absorbed (Prottey & Ferguson, 1975). Therefore including a default assumption of 1% for all modelled exposures will display a sufficient conservative approach. In addition it is assumed that only workers will come in contact with the neat substances.

 

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

                                       = oral NOAEL x 100/1

 

ABS: absorption

 

Assessment Factors were based on a sound scientific evaluation of available literature (ECETOC 2003 and Escher 2013 ).

Due to the fact that chronic and subchronic studies in rats resulted in comparable NOAELs/LOAELs (Munday et al., 1995a, b) no further assessment factor for exposure duration will be applied.