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
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
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:
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:
ECETOC, Technical Report No. 110
AF for intraspecies differences:
3
Justification:
ECETOC, Technical Report No. 110
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
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:
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:
ECETOC, Technical Report No. 110
AF for intraspecies differences:
3
Justification:
ECETOC, Technical Report No. 110
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
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

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.

As starting point the dietary NOAEL of 488 mg/kg bw/day (Mundayet al., 1976a) representing an average of all NOAELs, was chosen for the risk assessment. For details on study selection please refer to IUCLID section 7.5.

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

 

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. 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 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

 

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.

According to ECETOC, 2010 the use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently 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.

In general an AF of 2 is applied when extrapolating data of subchronic toxicity studies to the chronic situation. However, repeated dose toxicity data revealed comparable 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.

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
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:
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:
ECETOC, Technical Report No. 110
AF for intraspecies differences:
5
Justification:
ECETOC, Technical Report No. 110
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
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:
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:
ECETOC, Technical Report No. 110
AF for intraspecies differences:
5
Justification:
ECETOC, Technical Report No. 110
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
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
Value:
488 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 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:
ECETOC, Technical Report No. 110
AF for intraspecies differences:
5
Justification:
ECETOC, Technical Report No. 110
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

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.

As starting point the dietary NOAEL of 488 mg/kg bw/day (Mundayet al., 1976a) representing an average of all NOAELs, was chosen for the risk assessment. For details on study selection please refer to IUCLID section 7.5.

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.

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

According to ECETOC, 2010 the use of default AFs recommended by ECHA will in most cases lead to DNELs that are not scientifically justified and consequently 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.

In general an AF of 2 is applied when extrapolating data of subchronic toxicity studies to the chronic situation. However, repeated dose toxicity data revealed comparable 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.