Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.33 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):
25
Modified dose descriptor starting point:
NOAEC
Value:
83.17 mg/m³
Explanation for the modification of the dose descriptor starting point:
Since inhalation data are only available for IPA, an inhalation DNEL for LAS IPA was derived with a route-to route extrapolation, based on the chosen oral NOAEL.
AF for dose response relationship:
1
Justification:
no other uncertainties
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
incorporated in the calculation of the corrected inhalation NOAEC
AF for other interspecies differences:
2.5
Justification:
toxicokinetic/toxicodynamic differences
AF for intraspecies differences:
5
Justification:
DNEL derived for workers
AF for the quality of the whole database:
1
Justification:
the database is complete
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:
0.94 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
94 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal repeated-dose toxicity study is available either for LAS IPA. A route-to-route extrapolation from the oral NOAEL was chosen for the derivation of the dermal DNEL.
AF for dose response relationship:
1
Justification:
no other uncertainties
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to humans
AF for other interspecies differences:
2.5
Justification:
toxicokinetic/toxicodynamic differences
AF for intraspecies differences:
5
Justification:
DNEL for workers
AF for the quality of the whole database:
1
Justification:
the database is sufficient
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
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:
low hazard (no threshold derived)

Additional information - workers

According to ECHA’s guidance R.8 a leading DN(M)EL needs to be derived for the workers for every relevant route, duration and frequency of exposure, when this is feasible.

Acute toxicity data for LAS IPA indicate very low toxicity: in rats the oral LD50 is higher than 2000 mg/kg bw/day, while the dermal LD50 for LAS Na and for IPA when normalized for LAS IPA is also higher than 2000 mg/kg bw/day. The substance shall not be classified for oral and acute dermal toxicity, and hence no DNELacuteshall be derived.The long-term oral and dermal DNELs workers are considered sufficient for controlling any risks that may arise from exposure to LAS IPA. Inhalation exposure was considered the least relevant route, and high peak exposures through inhalation are not expected to occur.

LAS IPA is a skin irritant (Skin Irrit. 2, H315) and irritating to the eyes (Eye Irrit. 2, H319). However, no dose-response data are available and hence, a DNEL cannot be derived for these endpoints.

 

No repeated dose toxicity studies were performed with LAS IPA. The endpoint was addressed with data from LAS Na and IPA. Based on information from these two substances a NOAEL of 85 mg/kg bw (from a 9-month feeding study with LAS Na) was proposed for LAS IPA. Detailed explanation on this can be found on the repeated dose toxicity section.

 

The oral NOAEL for LAS IPA was calculated by scaling based on the molecular weight of the susbstance. The conversion factor from LAS Na is 1.11. The oral NOAEL LAS IPA is 94 mg/kg bw. This oral NOAEL for rats was used in order to extrapolate to a dermal NOAEL. There is no available information on the dermal absorption of LAS IPA, and hence,a worst case 100% absorption was applied for the Route-to-Route extrapolation. According to ECHA’s guidance Dose [concentration]-response regarding human health R.8.4.2 pag. 25 "On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. 1) should be introduced when performing oral-to-dermal extrapolation". Hence, NOAELdermal = oral NOAEL * ABSoral-rat/ABSoral-human <=> corrected NOAEL dermal = 94 * (1/1) = 94 mg/kg bw.

The following assessment factors were applied:

Allometric scaling (rat):              4     

Intraspecies (workers):             5    

Residual interspecies:                2.5  

Sub-chronic to chronic:             2    

AF total:                                   100

This results in a dermal DNELlong-termfor workers= 0.94 mg/kg bw/day.

 

Since inhalation data are only available for IPA, an inhalation DNEL was also derived on a route-to route extrapolation basis, based on the chosen oral NOAEL. In order to extrapolate from  an oral NOAEL to an inhalation NOAEC, absorption needs to be taken into account. There is no available information on the toxicokinetic behavior and absorption of LAS IPA, LAS Na or IPA within the pulmonary alveoli. ECHA’s guidance Dose [concentration]-response regarding human health R.8.4.2 pag. 25 states: "In the absence of substance-specific data on absorption, it is proposed, thus, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation". Besides the  absorption, the standard respiratory volume (sRV) needs to be considered, e.g. during 8 hours light activity at work the respiratory rate becomes higher than standard. This deviation is consistent with the assumption of a total breathing volume of 10 m3for an 8-hour shift and light activity at work. In the case of 8h exposure, it is assumed that the respiratory volume is 6.7 m3/person. The extrapolation from the sRV of rat to human is performed using the default assumption of 0.38 m3/kg bw (8 hours exposure):

 

corrected inhalation NOAEL= oral NOAEL * (1/sRVrat) * (ABSoral-rat/ABSinh-human) * (sRVhuman/wRV)<=> corrected inhalation NOAEL = 94 * (1/0.38 m3/kg/d) * (1/2) *(6.7 m3/10 m3) = 83.17 mg/m3,

 

where ABS: Absorption; sRV: standard Respiratory Volume; wRV: worker Respiratory Volume

To derive the inhalation DNEL, the same assessment factors as for the derivation of the oral and dermal DNEL were applied, except for the allometric scalling that has been already applied for the corrected inhalation NOAEL. The overall assessment factor is 25.

This results in an inhalation DNELlong-termfor workers= 3.33 mg/m3.

 

LAS IPA is not mutagenic and is not considered carcinogenic for humans. Based on the available data, LAS IPA is not considered a reproductive and developmental toxicant.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.82 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):
50
Modified dose descriptor starting point:
NOAEC
Value:
83.17 mg/m³
AF for dose response relationship:
1
Justification:
no other uncertainties
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
incorporated in the corrected inhalation NOAEC
AF for other interspecies differences:
2.5
Justification:
toxicokinetic/toxicodynamic differences
AF for intraspecies differences:
10
Justification:
DNEL for the general population
AF for the quality of the whole database:
1
Justification:
the database is sufficient
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:
0.47 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):
200
Modified dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:
No dermal repeated-dose toxicity study is available either for LAS IPA, LAS Na or IPA. A route-to-route extrapolation from the oral NOAEL was chosen for the derivation of the dermal DNEL.
AF for dose response relationship:
1
Justification:
no other uncertainties
AF for differences in duration of exposure:
2.5
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to humans
AF for other interspecies differences:
2
Justification:
toxicokinetic/toxicodynamic differences
AF for intraspecies differences:
10
Justification:
DNEL for general population
AF for the quality of the whole database:
1
Justification:
the data base is sufficient
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
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:
0.47 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):
200
Modified dose descriptor starting point:
NOAEL
Value:
94 mg/kg bw/day
AF for dose response relationship:
1
Justification:
no other uncertainties
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to humans
AF for other interspecies differences:
2.5
Justification:
toxicokinetic/toxicodynamic differences
AF for intraspecies differences:
10
Justification:
DNEL for general population
AF for the quality of the whole database:
1
Justification:
the data base is sufficient
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:
low hazard (no threshold derived)

Additional information - General Population

According to ECHA’s guidance R.8 a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, when this is feasible.

LAS IPA is a skin irritant (Skin Irrit. 2, H315) and irritating to the eyes (Eye Irrit. 2, H319). However, no dose-response data are available and hence, a DNEL cannot be derived for these endpoints.

 

No repeated dose toxicity studies were performed with LAS IPA. The endpoint was addressed with data from LAS Na and IPA. Based on information from these two substances a NOAEL of 85 mg/kg bw (from a 9-month feeding study with LAS Na) was proposed for LAS IPA. Detailed explanation on this can be found on the repeated dose toxicity section.

 

The oral NOAEL for LAS IPA was calculated by scaling based on the molecular weight of the susbstance. The conversion factor from LAS Na is 1.11. The oral NOAEL LAS IPA is 94 mg/kg bw.

Assessment factors used:

Allometric scaling (rat):              4     

Intraspecies (gen. pub.):             10    

Residual interspecies:                2.5  

Sub-chronic to chronic:             2    

AF total:                                   200

This results in an oral DNELlong-termfor general population= 0.47 mg/kg bw/day.

 

The oral NOAEL for rats (94 mg/kg bw) was used in order to extrapolate to a dermal NOAEL. There is no available information on the dermal absorption of LAS IPA, and hence,a worst case 100% absorption was applied for the Route-to-Route extrapolation. According to ECHA’s guidance Dose [concentration]-response regarding human health R.8.4.2 pag. 25 "On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e. 1) should be introduced when performing oral-to-dermal extrapolation". Hence, NOAELdermal = oral NOAEL * ABSoral-rat/ABSoral-human <=> corrected NOAEL dermal = 94 * (1/1) = 94 mg/kg bw. The same assessment factors used for the derivation of the oral DNEL were applied. This results in a dermal DNELlong-termfor general population= 0.47 mg/kg bw/day.

 

Since inhalation data are only available for IPA, an inhalation DNEL was also derived on a route-to route extrapolation basis, based on the chosen oral NOAEL. In order to extrapolate from  an oral NOAEL to an inhalation NOAEC, absorption needs to be taken into account. There is no available information on the toxicokinetic behavior and absorption of LAS IPA, LAS Na or IPA within the pulmonary alveoli. ECHA’s guidance Dose [concentration]-response regarding human health R.8.4.2 pag. 25 states: "In the absence of substance-specific data on absorption, it is proposed, thus, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation". The extrapolation from the sRV of rat to human is performed using the default assumption of 1.15 m3/kg bw (24 hours exposure). Hence:

 corrected inhalation NOAEL = oral NOAEL * (1/sRVrat) * (ABSoral-rat/ ABSinh-human) <=> corrected inhalation NOAEL = 94 * (1/1.15) * (1/2) = 41 mg/m3, where ABS: Absorption; sRV: standard Respiratory Volume.

To derive the inhalation DNEL for the general public, the same assessment factors as for the derivation of the oral and dermal DNEL were applied, except for the allometric scalling that has been already applied for the corrected inhalation NOAEL.

This results in an inhalation DNELlong-termfor generl public= 0.82 mg/m3

 

LAS IPA is not mutagenic and is not considered carcinogenic for humans. Based on the available data, LAS IPA is not considered a reproductive and developmental toxicant.