Registration Dossier

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
DNEL related information
Overall assessment factor (AF):
3
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
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
DNEL related information
Overall assessment factor (AF):
12
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Correction of dose descriptors (route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific DNELs

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 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:

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.

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 C12ASO4Na 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.

Since short-term exposure scenarios will not be assessed, only long-term DNELs for workers and the general population 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. 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.

It is believed 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 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 consequently they should be used preferentially.

Due to the fact that chronic studies in rats resulted in equal NOAELs (Munday et al., 1995) no further assessment factor for exposure duration will be applied.

 

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
DNEL related information
Overall assessment factor (AF):
5
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
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
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

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
DNEL related information
Overall assessment factor (AF):
20
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Correction of dose descriptors (route-to-route extrapolation), application of assessment factors and derivation of the endpoint specific DNELs

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 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:

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.

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 C12ASO4Na 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.

 

Since short-term exposure scenarios will not be assessed, only long-term DNELs for workers and the general population 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. 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.

It is believed 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 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 consequently they should be used preferentially.

Due to the fact that chronic studies in rats resulted in equal NOAELs (Munday et al., 1995) no further assessment factor for exposure duration will be applied.