Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
152.22 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR No. 110
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
Value:
456.66 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.38 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h)). ABSoral-rat = oral absorption rate in rats, ABSinh-human = inhalation absorption rate in humans.

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity study
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling already included in ECHA starting point derivation method; no further factor required.
AF for other interspecies differences:
1
Justification:
According to ECETOC TR No. 110
AF for intraspecies differences:
3
Justification:
According to ECETOC TR No. 110
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 158.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR No. 110
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Value:
25 900 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=NOAELoral*( ABSoral-rat/ABSdermal-human). ABSoral-rat = oral absorption rate in rats, ABSdermal-human = dermal absorption rate in humans.

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on a study in rat
AF for other interspecies differences:
1
Justification:
According to ECETOC TR No. 110
AF for intraspecies differences:
3
Justification:
According to ECETOC TR No. 110
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
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

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", May 2008.

 

The NOAEL of 259 mg/kg bw/day for female rats, derived from a 2 year feeding study, served as basis for the extrapolations. The slightly higher NOAEL for females (males 195 mg/kg bw/day) was chosen as this reflected the highest dose tested, and differences in dose height compared to the male animals occurred due to differences in food uptake. It is justified to assume that the males would have not shown symptoms of toxicity, either, if dosed with the same amount as taken up by feed by the females. This view is supported by peer-reviewed data reporting NOAELs of 500 and 1000 mg/kg bw/day from subchronic studies.

 

Within 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 electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to 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.

 

In order 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 percutaneous absorption of Alpha Olefin Sulfonate was measured in a dermal absorption study in the rat in vivo (Minegishi, 1977). In this study an 0.2% dilution of Alpha Olefin Sulfonate was applied to the intact skin, and after 24 hours 0.62% of the applied Alpha Olefin Sulfonate was recovered from urine, bile and the main organs. Therefore, assuming a dermal absorption of 1.0% via the intact skin displays a sufficient conservative approach.

 

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. The substance is most frequently marketed in forms of aqueous solutions, thus, it is assumed that only workers will come into contact with the neat substance and with 34 to 40% solutions. Based on the low vapour pressure of the aqueous solutions, exposure via the inhalative route is unlikely. If handled in powder form it is common to use personal protective equipment like dust masks to avoid inhalation due to the known irritating potential of the substance; therefore, derivation of short-term systemic and local DNELs for inhalation can be omitted. Due to the known irritating potential of the concentrated solutions and the neat solid, it is common to use personal protective equipment like gloves to avoid dermal contact; therefore, considering local dermal DNELs can be omitted.

 

It is assumed that use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently lead to unrealistically low exposure levels for establishing safe use. Moreover, ECHA provides limited scientific justification for the default AFs; it is supposed they have relied on 'standard approaches' used by other organisations. In contrast, ECETOC based its AFs on a critical review of the literature; in consequence they should be used preferentially. There is no difference in the AFs proposed by REACH TGD and ECETOC for allometric scaling, but REACH TGD requests an additional interspecies AF of 2.5 in combination with the intraspecies AFs of 5 for workers. In contrast, ECETOC proposed an overall factor of 3 for the workplace. According to the argumentation given in Chapter 3 of ECETOC Technical Report No. 110, a separate AF for 'remaining' interspecies differences is unnecessary because inter- and intraspecies variability are not independent variables. ECETOC recommends using allometric scaling and the 5th percentile of the human distribution of intraspecies variability. Consequently, the 'remaining' uncertainty for interspecies variability is already accounted for by the intraspecies AF (Calabrese, 1985; Hattis et al, 1987). The interdependency of the AF for inter- and intraspecies variability was shown by Calabrese and Gilbert (1993). They demonstrated that a simple multiplication of both (unmodified) AF is inappropriate. Therefore, both AF may be considered in conjunction or even combined.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
45.04 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR No. 110
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
Value:
225.22 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/1.15 m³/kg bw/day)*(ABSoral-rat/ABSinh-human). ABSoral-rat = oral absorption rate in rats, ABSinh-human = inhalation absorption rate in humans.

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity study
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling already included in ECHA starting point derivation method; no further factor required.
AF for other interspecies differences:
1
Justification:
According to ECETOC TR No. 110
AF for intraspecies differences:
5
Justification:
According to ECETOC TR No. 110
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 295 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC TR No. 110
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Value:
25 900 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = NOAELoral*( ABSoral-rat/ABSdermal-human). ABSoral-rat = oral absorption rate in rats, ABSdermal-human = dermal absorption rate in humans.

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on a study in rat
AF for other interspecies differences:
1
Justification:
According to ECETOC TR No. 110
AF for intraspecies differences:
5
Justification:
According to ECETOC TR No. 110
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
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:
12.95 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECETOC Technical Report No. 110
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Value:
259 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation needed

AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity study
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on a study in rat
AF for other interspecies differences:
1
Justification:
According to ECETOC TR No. 110
AF for intraspecies differences:
5
Justification:
According to ECETOC TR No. 110
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

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", May 2008.

The NOAEL of 259 mg/kg bw/day for female rats, derived from a 2 year feeding study, served as basis for the extrapolations. The slightly higher NOAEL for females (males 195 mg/kg bw/day) was chosen as this reflected the highest dose tested, and differences in dose height compared to the male animals occurred due to differences in food uptake. It is justified to assume that the males would have not shown symptoms of toxicity, either, if dosed with the same amount as taken up by feed by the females. This view is supported by peer-reviewed data reporting NOAELs of 500 and 1000 mg/kg bw/day from subchronic studies.

Within 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 electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to 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.

In order 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 percutaneous absorption of Alpha Olefin Sulfonate was measured in a dermal absorption study in the rat in vivo (Minegishi, 1977). In this study an 0.2% dilution of test item was applied to the intact skin, and after 24 hours 0.62% of the applied Alpha Olefin Sulfonate was recovered from urine, bile and the main organs. Therefore, assuming a dermal absorption of 1.0% via the intact skin displays a sufficient conservative approach.

Since short-term exposure scenarios will not be assessed, only long-term DNELs for the general population are derived. The general population will not come into contact with the neat substance. The maximum concentration of Sulfonic acids, C14-16 (even numbered)-alkane hydroxy and C14-16 (even numbered)-alkene, sodium salts in consumer products is 16%. The registered substance is classified for skin irritation at a generic concentration limit of > 5%. The available data for this effect do not provide quantitative dose-response information; thus, no local DNELs have been derived for dermal exposure. Exposure assessment and risk characterisation are performed on a qualitative basis.

It is assumed that use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently lead to unrealistically low exposure levels for establishing safe use. Moreover, ECHA provides limited scientific justification for the default AFs; it is supposed they have relied on 'standard approaches' used by other organisations. In contrast, ECETOC based its AFs on a critical review of the literature; in consequence they should be used preferentially. There is no difference in the AFs proposed by REACH TGD and ECETOC for allometric scaling, but REACH TGD requests an additional interspecies AF of 2.5 in combination with the intraspecies AFs of 10 for the general population. In contrast, ECETOC proposed an overall factor of 5 for the general population. According to the argumentation given in Chapter 3 of ECETOC Technical Report No. 110, a separate AF for 'remaining' interspecies differences is unnecessary because inter- and intraspecies variability are not independent variables. ECETOC recommends using allometric scaling and the 5th percentile of the human distribution of intraspecies variability. Consequently, the 'remaining' uncertainty for interspecies variability is already accounted for by the intraspecies AF (Calabrese, 1985; Hattis et al, 1987). The interdependency of the AF for inter- and intraspecies variability was shown by Calabrese and Gilbert (1993). They demonstrated that a simple multiplication of both (unmodified) AF is inappropriate. Therefore, both AF may be considered in conjunction or even combined.