Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
175 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
DNEL value:
530 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:
Chronic and subchronic studies resulted in comparable NOAELs. For details refer to discussion.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not needed for inhalation route.
AF for other interspecies differences:
1
Justification:
For details refer to discussion.
AF for intraspecies differences:
3
Justification:
For details refer to 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:
2 750 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
DNEL value:
33 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Adequate route specific dose descriptor is not available. For details refer to discussion.
AF for dose response relationship:
1
Justification:
NOAEL is chosen as starting point.
AF for differences in duration of exposure:
1
Justification:
Chronic and subchronic studies resulted in comparable NOAELs. For details refer to discussion.
AF for interspecies differences (allometric scaling):
4
Justification:
Species: rat
AF for other interspecies differences:
1
Justification:
For details refer to discussion.
AF for intraspecies differences:
3
Justification:
For details refer to discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
132 µg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
NOAEL is chosen as starting point.
AF for differences in duration of exposure:
1
Justification:
Default value for local effects (ECHA REACh Guidance, Chapter R.8).
AF for interspecies differences (allometric scaling):
1
Justification:
Default value for local effects (ECHA REACh Guidance, Chapter R.8).
AF for other interspecies differences:
1
Justification:
Default value for local effects (ECHA REACh Guidance, Chapter R.8).
AF for intraspecies differences:
3
Justification:
For details refer to discussion.
Acute/short term exposure
Hazard assessment conclusion:
low 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

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, Version 2.1, November 2012) were used when applicable to derive the DNELs. Several AFs for which there is additional information were refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant.

Conversion of oral NOAEL to inhalatory NAEC

As starting point the NOAEL of 300 mg/kg bw/day of the 2 generation drinking water study (Biggs et al., 1999) was chosen for the risk assessment. For details on study selection please refer to IUCLID section 7.5.

Since there is no dose descriptor for every exposure route, dose descriptors were converted into a corrected 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 (300 mg/kg bw/d) into an inhalatory NAEC is performed using the following equations; for workers the resulting concentration needs to be additionally corrected for the differences in basal respiratory rate and respiratory rate under light activity:

Corrected inhalatory NAEC = oral NOAEL x1/sRVratx ABSoral-rat/ABSinh-humanxsRVhuman/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 300 *6.7 / (10 x 0.38) = 530 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 gastrointestinal tract. More lipophilic substances may be better absorbed in the gastrointestinal 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. It is assumed that the absorption rate of AES after oral application is almost complete (100%, 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 when extrapolating from oral to inhalation route.

A factor of 1 for the differences in exposure duration was applied. The subchronic study revealed a NOAEL of 100 mg/kg bw/d (Ashby, 1977), while the NOAEL chosen as starting point from a subchronic study was 300 mg/kg bw/d (Biggs, 1999). However, the dose of 100 mg/kg bw/d within the chronic study was 11 times lower than the next higher dose. Therefore, this value is unreasonably low due to dose spacing within the subchronic study. Additionally, the LOAEL of the subchronic study (1100 mg/kg bw/d) exceeds the NOAELs of the subchronic studies by at least two times. As the subchronic NOAELs (ranging from 225 to 600 mg/kg bw/d) represented always the highest dose level, a factor for time extrapolation is not needed.

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. As a consequence, the adjustment of interspecies AF to account for the differences noted in such analyses is not scientifically justified. Therefore, although residual interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). For this total (inter- and intraspecies) variability, ECETOC proposed an overall factor of 3 for the workplace and of 5 for the general population. Therefore, a separate residual AF for interspecies is unnecessary because it is already accounted for by the intraspecies assessment factor (Calabrese, 1985; Hattis et al, 1987). 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.

Thus, following factors were applied for interspecies differences (1) and intraspecies differences (3).

The inhalatory DNEL is calculated to be 175 mg/m3.

 Conversion of oral NOAEL to dermal NAEL for systemic toxicity

The dose levels within the repeated dermal toxicity study of Cardin (1978) were chosen to produce slight irritation of the skin. The dose level of the second repeated dose dermal toxicity study (Ligntowler, 1976) was even lower. Indeed, both studies revealed signs of skin irritation but the doses did not produce any signs of systemic toxicity. Therefore, these NOAELs are not reliable to derive long-term systemic effects and the NOAELs from the repeated oral toxicity studies had to be considered for risk assessment.

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 AES is relatively poor as can be expected from an ionic molecule (HERA, 2003). The percutaneous absorption of sodium laureth sulfate (SLS = NaC12AES) was measured in a human in vitro and a rat in vivo study (Aulmann, 1996; Zengerly, 2009).

In the in vitro study with human skin of 3 different donors according to OECD Guideline 428 most of the 10% tenside dilution remained on the skin surface, a small amount penetrated into the Stratum corneum, an even smaller amount reached the deeper skin layers and no tenside could be quantified in the receptor compartment. The mean absorbed dose of SLS, sum of the amounts found in the viable epidermis, dermis and receptor medium and the mean recovery of SLS found in the deeper skin layers sum up to 0.56%.

The in vivo study for percutaneous absorption of SLS was performed in Wistar rats with 35S-labelled test substance as a 1% aqueous solution. Under the use conditions (rinse off after 15 minutes), only 0.1% of the applied surfactant was absorbed. In another assay, the test substance was not rinsed off for 48 h. Here, 0.9% of the applied test substance was absorbed through the rat skin. Thus, also under these stringent conditions, absorption is considered to be very low. Considering that the in vivo test was done with a 1% dilution, the test substance was not rinsed off after 15 minutes (stringent conditions) and that the skin permeability across the species decreases from rat to human, assuming a dermal absorption of 0.9% displays a sufficient conservative approach.

Thus, an absorption rate of 0.9 % 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% / 0.9%

ABS: absorption

Thus, the corrected starting point for dermal route was 300 x 100 / 0.9 = 33000 mg/kg bw/d.

DNEL derivation using the dermal NAEC

A factor of 1 for the differences in exposure duration was applied. The chronic study revealed a NOAEL of 100 mg/kg bw/d, while the NOAEL chosen as starting point from a subchronic study was 300 mg/kg bw/d. However, the dose of 100 mg/kg bw/d within the chronic study was factor 11 lower than the next higher dose. Therefore, this value is unreasonably low due to dose spacing within the chronic study. Additionally, the LOAEL of the chronic study (1100 mg/kg bw/d) exceeds the NOAELs of the subchronic studies by at least a factor of 2. As the subchronic NOAELs (ranging from 225 to 600 mg/kg bw/d) represented always the highest dose level, a factor for time extrapolation is not needed.

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. As a consequence, the adjustment of interspecies AF to account for the differences noted in such analyses is not scientifically justified. Therefore, although residual interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). For this total (inter- and intraspecies) variability, ECETOC proposed an overall factor of 3 for the workplace and of 5 for the general population. Therefore, a separate residual AF for interspecies is unnecessary because it is already accounted for by the intraspecies assessment factor (Calabrese, 1985; Hattis et al, 1987). These assumptions are 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.

Thus, following factors were applied for allometric scaling (4), interspecies differences (1) and intraspecies differences (3).

The dermal systemic DNEL is calculated to be 2750 mg/kg bw/d.

DNEL derivation of dermal long-term local effects

Data of the repeated dose dermal toxicity study (Cardin, 1978) showed signs of irritation, i.e. minimal to slight acanthosis at the application site at 6.91 mg/d. No effects were observed at 2.38 mg/d. As the amount was distributed over an area of 6 cm2 this dose corresponds to 397 µg/cm2. The severity of the effect cannot be further assessed as no scoring system for acanthosis is available. Local exposure is assumed to be sufficiently covered as irritating properties of AES are assessed qualitatively. Nevertheless, the DNEL was derived for sake of completeness.

Short-term exposure scenarios will not be assessed. Only long-term DNELs for workers are considered to be relevant (Table 1). The oral route is not relevant for workers.

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

 

Table 1: Corrected dose descriptors per endpoint for workers

Endpoint

Route

Most relevant quantitative dose descriptor

Corrected dose descriptor

Local

Systemic

Local

Systemic

2-Gen study, oral

dermal

NA

NOAELoral= 300 mg/kg bw

NA

NAELdermal= 33,000 mg/kg bw

inhalation

NA

NOAELoral= 300 mg/kg bw

NA

NAEC = 530 mg/m3

NA: not applicable

 

 

Escher et al. 2013, In Press

Interspecies extrapolation based on the RepDose database-A probabilistic approach.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
52 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
DNEL value:
260 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:
Chronic and subchronic studies resulted in comparable NOAELs. For details refer to discussion.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not needed for inhalation route.
AF for other interspecies differences:
1
Justification:
For details refer to discussion.
AF for intraspecies differences:
5
Justification:
For details refer to discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
1 650 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
DNEL value:
33 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Adequate route specific dose descriptor is not available. For details refer to discussion.
AF for dose response relationship:
1
Justification:
NOAEL is chosen as starting point.
AF for differences in duration of exposure:
1
Justification:
Chronic and subchronic studies resulted in comparable NOAELs. For details refer to discussion.
AF for interspecies differences (allometric scaling):
4
Justification:
Species: rat
AF for other interspecies differences:
1
Justification:
For details refer to discussion.
AF for intraspecies differences:
5
Justification:
For details refer to discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
79 µg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
NOAEL is chosen as starting point.
AF for differences in duration of exposure:
1
Justification:
Default value for local effects (ECHA REACh Guidance, Chapter R.8).
AF for interspecies differences (allometric scaling):
1
Justification:
Default value for local effects (ECHA REACh Guidance, Chapter R.8).
AF for other interspecies differences:
1
Justification:
Default value for local effects (ECHA REACh Guidance, Chapter R.8).
AF for intraspecies differences:
5
Justification:
For details refer to discussion.
Acute/short term exposure
Hazard assessment conclusion:
low 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:
15 mg/kg bw/day
Most sensitive endpoint:
effect on fertility
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 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
Justification:
Chronic and subchronic studies resulted in comparable NOAELs. For details refer to discussion.
AF for interspecies differences (allometric scaling):
4
Justification:
Species: rat
AF for other interspecies differences:
1
Justification:
For details refer to discussion.
AF for intraspecies differences:
5
Justification:
For details refer to discussion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

In general, assessment factors (AF) recommended by ECHA (Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose[concentration]-response for human health. European Chemicals Agency, Version 2.1, November 2012) were used when applicable to derive the DNELs. Several AFs for which there is additional information were refined. The difference in metabolic rate between humans and the test species has been taken into account, where relevant.

Conversion of oral NOAEL to inhalatory NAEC

As starting point the NOAEL of 300 mg/kg bw/day of the 2 generation drinking water study (Biggs et al., 1999) was chosen for the risk assessment. For details on study selection please refer to IUCLID section 7.5.

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 into an inhalatory NAEC is performed using the following equations:

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 300 /1.15 = 260 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. The consideration of physico-chemical parameters should be performed before using default assumptions. It is assumed that the absorption rate of AES after oral application is almost complete (100%, 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 when extrapolating from oral to inhalation route.

A factor of 1 for the differences in exposure duration was applied. The subchronic study revealed a NOAEL of 100 mg/kg bw/d (Ashby, 1977), while the NOAEL chosen as starting point from a subchronic study was 300 mg/kg bw/d (Biggs, 1999). However, the dose of 100 mg/kg bw/d within the chronic study was 11 times lower than the next higher dose. Therefore, this value is unreasonably low due to dose spacing within the subchronic study. Additionally, the LOAEL of the chronic study (1100 mg/kg bw/d) exceeds the NOAELs of the subchronic studies by at least two times. As the subchronic NOAELs (ranging from 225 to 600 mg/kg bw/d) represented always the highest dose level, a factor for time extrapolation is not needed.

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. As a consequence, the adjustment of interspecies AF to account for the differences noted in such analyses is not scientifically justified. Therefore, although residual interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). For this total (inter- and intraspecies) variability, ECETOC proposed an overall factor of 3 for the workplace and of 5 for the general population. Therefore, a separate residual AF for interspecies is unnecessary because it is already accounted for by the intraspecies assessment factor (Calabrese, 1985; Hattis et al, 1987). 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.

Thus, following factors were applied for interspecies differences (1) and intraspecies differences (5).

The inhalatory DNEL is calculated to be 52 mg/m3.

Conversion of oral NOAEL to dermal NAEL for systemic toxicity 

The dose levels within the repeated dermal toxicity study of Cardin (1978) were chosen to produce slight irritation of the skin. The dose level of the second repeated dose dermal toxicity study (Ligntowler, 1976) was even lower. Indeed, both studies revealed signs of skin irritation but the doses did not produce any signs of systemic toxicity. Therefore, these NOAELs are not reliable to derive long-term systemic effects and the NOAELs from the repeated oral toxicity studies had to be considered for risk assessment.

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 AES is relatively poor as can be expected from an ionic molecule (HERA, 2003). The percutaneous absorption of sodium laureth sulfate (SLS = NaC12AES) was measured in a human in vitro and a rat in vivo study (Aulmann, 1996; Zengerly, 2009).

In the in vitro study with human skin of 3 different donors according to OECD Guideline 428 most of the 10% tenside dilution remained on the skin surface, a small amount penetrated into the Stratum corneum, an even smaller amount reached the deeper skin layers and no tenside could be quantified in the receptor compartment. The mean absorbed dose of SLS, sum of the amounts found in the viable epidermis, dermis and receptor medium and the mean recovery of SLS found in the deeper skin layers sum up to 0.56%.

The in vivo study for percutaneous absorption of SLS was performed in Wistar rats with35S-labelled test substance as a 1% aqueous solution. Under the use conditions (rinse off after 15 minutes), only 0.1% of the applied surfactant was absorbed. In another assay, the test substance was not rinsed off for 48 h. Here, 0.9% of the applied test substances was absorbed through the rat skin. Thus, also under these stringent conditions, absorption is considered to be very low.

Considering that the in vivo test was done with a 1% dilution, the test substance was not rinsed off after 15 minutes (stringent conditions) and that the skin permeability across the species decreases from rat to human, assuming a dermal absorption of 0.9% displays a sufficient conservative approach.

Thus, an absorption rate of 0.9 % 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% / 0.9%

 

ABS: absorption

Thus, the corrected starting point for dermal route was 300 x 100 / 0.9 = 33000 mg/kg bw/d.

DNEL derivation using the dermal NAEC

A factor of 1 for the differences in exposure duration was applied. The chronic study revealed a NOAEL of 100 mg/kg bw/d, while the NOAEL chosen as starting point from a subchronic study was 300 mg/kg bw/d. However, the dose of 100 mg/kg bw/d within the chronic study was factor 11 lower than the next higher dose. Therefore, this value is unreasonably low due to dose spacing within the chronic study. Additionally, the LOAEL of the chronic study (1100 mg/kg bw/d) exceeds the NOAELs of the subchronic studies by at least a factor of 2. As the subchronic NOAELs (ranging from 225 to 600 mg/kg bw/d) represented always the highest dose level, a factor for time extrapolation is not needed.

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. As a consequence, the adjustment of interspecies AF to account for the differences noted in such analyses is not scientifically justified. Therefore, although residual interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). For this total (inter- and intraspecies) variability, ECETOC proposed an overall factor of 3 for the workplace and of 5 for the general population. Therefore, a separate residual AF for interspecies is unnecessary because it is already accounted for by the intraspecies assessment factor (Calabrese, 1985; Hattis et al, 1987). These assumptions are 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.

Thus, following factors were applied for allometric scaling (4), interspecies differences (1) and intraspecies differences (5).

The dermal systemic DNEL is calculated to be 1650 mg/kg bw/d.

DNEL derivation of dermal long-term local effects

Data of the repeated dose dermal toxicity study (Cardin, 1978) showed signs of irritation, i.e. minimal to slight acanthosis at the application site at 6.91 mg/d. No effects were observed at 2.38 mg/d. As the amount was distributed over an area of 6 cm2 this dose corresponds to 397 µg/cm2. The severity of the effect cannot be further assessed as no scoring system for acanthosis is available. Local exposure is assumed to be sufficiently covered as only workers will come into contact with undiluted, irritating AES. Nevertheless, the DNEL was derived for sake of completeness.

DNEL derivation for oral route

A factor of 1 for the differences in exposure duration was applied. The chronic study revealed a NOAEL of 100 mg/kg bw/d, while the NOAEL chosen as starting point from a subchronic study was 300 mg/kg bw/d. However, the dose of 100 mg/kg bw/d within the chronic study was factor 11 lower than the next higher dose. Therefore, this value is unreasonably low due to dose spacing within the chronic study. Additionally, the LOAEL of the chronic study (1100 mg/kg bw/d) exceeds the NOAELs of the subchronic studies by at least a factor of 2. As the subchronic NOAELs (ranging from 225 to 600 mg/kg bw/d) represented always the highest dose level, a factor for time extrapolation is not needed.

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. As a consequence, the adjustment of interspecies AF to account for the differences noted in such analyses is not scientifically justified. Therefore, although residual interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). For this total (inter- and intraspecies) variability, ECETOC proposed an overall factor of 3 for the workplace and of 5 for the general population. Therefore, a separate residual AF for interspecies is unnecessary because it is already accounted for by the intraspecies assessment factor (Calabrese, 1985; Hattis et al, 1987). These assumptions are 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.

Thus, following factors were applied for allometric scaling (4), interspecies differences (1) and intraspecies differences (5).

The oral systemic DNEL is calculated to be 15 mg/kg bw/d.

Short-term exposure scenarios will not be assessed. Only long-term DNELs for the general population are considered to be relevant (Table 1). It is assumed that only workers will come in contact with the neat substances, therewith considering local DNELs as obsolete.

Table1: Corrected dose descriptors per endpoint for the general population

Endpoint

Route

Most relevant quantitative dose descriptor

Corrected dose descriptor

Local

Systemic

Local

Systemic

2-Gen study, oral

oral

NA

NOAELoral= 300 mg/kg bw

NA

NA

dermal

NA

NOAELoral= 300 mg/kg bw

NA

NAELdermal= 33,000 mg/kg bw

inhalation

NA

NOAELoral= 300 mg/kg bw

NA

NAEC = 260 mg/m3

NA: not applicable

References:

Escher et al. 2013, In Press

Interspecies extrapolation based on the RepDose database-A probabilistic approach.