Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., compds. with isopropanolamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.45 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:

86.18 mg/m³

AF for dose response relationship:

1

Justification:

no other uncertainties

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic

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:

0.98 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:

97.75 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 MIPA. 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 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:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high 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 and every relevant route, duration and frequency of exposure, when this is feasible.

Acute toxicity data for LAS MIPA indicate low toxicity. Based on the data, LAS MIPA shall be labelled for acute oral toxicity (Acute Tox. 4, H302). However, there is no potential for high peak exposures and thus, an oral DNEL_acuteis considered superfluous.

The substance is not classified for acute dermal toxicity, and hence, no dermal DNEL_acuteshall be derived.The long-term dermal and oral DNELs for workers are considered sufficient for controlling any risks that may arise from exposure to LAS MIPA. Inhalation exposure was considered the least relevant route, and similarly high peak exposures through inhalation are not expected to occur.

LAS MIPA is a not a skin irritant based on the two in vitro tests performed. The in vitro eye irritation test suggests irritating properties of the test substance. However, eye damaging properties cannnot be excluded on the basis of this test, since it is not so far accepted on regulatory grounds. Therefore, LAS MIPA shall be labelled as damaging to the eyes (Eye Dam. 1, H318). No dose-response data are available and hence, a DNEL cannot be derived for this endpoint.

 

No repeated dose toxicity studies were performed with LAS MIPA. The endpoint was addressed with data from LAS Na, HCl MIPA, and DIPA. There are three repeated dose oral toxicity studies with LAS Na.  The lowest LOAEL is from the 6-month rat study (Yoneyama et al., 1972) with a LOAEL of 115 mg/kg bw.  The highest NOAEL below this LOAEL is from the 9-month rat study (Yoneyama et al., 1976) with NOAEL = 85 mg/kg bw, based on histological changes seen in the kidney. In view of the available information it is not possible to determine which single study among those is the most reliable or appropriate for the determination of a NOAEL. Therefore, based on the data from all the studies, a NOAEL of 85 mg/kg bw is proposed, which was derived from a 9- month oral study and corresponds to the NOAEL, which is closest to the lowest available oral LOAEL of 115 mg/kg bw.The NOAELs observed in the repeated dose studies with HCl MIPA (28 days) and DIPA (90 days) were 300 and 100 mg/kg bw, respectively. In the 28 day study anemic effects were seen in male animals. In the 90 day study with DIPA, absolute and relative kidney weights were significantly increased; nonetheless, these kidney effects were not accompanied by any histological changes in the kidney, in the whole dosing regimen. It can therefore be stated that the two substances, LAS Na and DIPA, although they both give rise to effects on the kidney, they induce effects with different mechanisms and modes of action. Consequently, there is no need to derive a NOAEL based on considerations of combination toxicity - the lowest NOAEL observed, since NOAELs presuppose absence of effects, is protective for all MoAs.  On this basis, the NOAEL of 85 mg/kg bw for Las Na, is also a safe level for LAS MIPA. The same holds for the anemic effects observed in the study with HCl MIPA, at a much higher dose level of 300 mg/kg bw (NOAEL: 300 mg/kg bw). Based on this reasoning the NOAEL= 85 mg/kg bw/day from the oral repeated-dose (9 months) toxicity study with LAS Na was used for the derivation of a long-term DNEL for LAS MIPA.

The oral NOAEL for LAS MIPA was calculated by scaling based on the molecular weight of the susbstance: oral NOAEL LAS MIPA = 97.75 mg/kg bw. This oral NOAEL was used in order to extrapolate to a dermal NOAEL. There is no available information on the dermal absorption of LAS MIPA or MIPA, and hence, an 100% dermal absorption was assumed and used for the route-to-route extrapolation for systemic effects. ECHA’s guidance Dose [concentration]-response regarding human health R.8.4.2 pag. 25 states that "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":

dermal NOAEL = oral NOAEL * ABSoral-rat/ABSoral-human <=> corrected dermal NOAEL= 97.75* (1/1) = 97.75 mg/kg bw.

Assessment factors used:

Allometric scaling (rat):             4     

Intraspecies (workers):             5   

Residual interspecies:                2.5  

Sub-chronic to chronic:            2    

AF total:                                  100

This results in a dermal DNEL_long-term= 0.98 mg/kg bw for workers.

Since no inhalation data are available, cause it not the most relevant exposure route, an inhalation DNEL was also derived on a route-to route extrapolation basis.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 MIPA, LAS Na or MIPA 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) * (ABS_oral-rat/ABS_inh-human) * sRV_human/wRV<=>

corrected inhalation NOAEL = 97.75 * (1/0.38 m³/kg/d) * (1/2) *(6.7 m³/10 m³) = 86.18 mg/m³(page 27), 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 DNEL_long-term= 3.45 mg/m³ for workers.

LAS MIPA is not mutagenic and is not considered carcinogenic for humans.Based on the available data, LAS MIPA is not considered a reproductive and developmental toxicant. No DNELs were established.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.85 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:

42.5 mg/m³

AF for dose response relationship:

1

Justification:

no other uncertainties

AF for differences in duration of exposure:

2

Justification:

sub-chronic to chronic

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 data base 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:

0.49 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:

97.75 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 MIPA, LAS Na or MIPA. 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:

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:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.49 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:

97.75 mg/kg bw/day

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:

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:

low hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high 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.

Acute toxicity data for LAS MIPA indicate low toxicity. Based on the data, LAS MIPA shall be labelled for acute oral toxicity (Acute Tox. 4, H302). However, there is no potential for high peak exposures and thus, an oral DNEL_acuteis not necessary.

The substance is not classified for acute dermal toxicity, and hence, no dermal DNEL_acuteshall be derived. The long-term dermal and oral DNELs for workers are considered sufficient for controlling any risks that may arise from exposure to LAS MIPA. Inhalation exposure was considered the least relevant route, and similarly high peak exposures through inhalation are not expxted to occur.

LAS MIPA is a not a skin irritant based on the two in vitro tests performed. The in vitro eye irritation test suggests irritating properties of the test substance. However, eye damaging properties cannnot be excluded on the basis of this test, since it is not so far accepted on regulatory grounds. Therefore, LAS MIPA shall be labelled as damaging to the eyes (Eye Dam. 1, H318). No dose-response data are available and hence, a DNEL cannot be derived for this endpoint.

 

No repeated dose toxicity studies were performed with LAS MIPA. The endpoint was addressed with data from LAS Na, HCl MIPA, and DIPA. There are three repeated dose oral toxicity studies with LAS Na.  The lowest LOAEL is from the 6-month rat study (Yoneyama et al., 1972) with a LOAEL of 115 mg/kg bw.  The highest NOAEL below this LOAEL is from the 9-month rat study (Yoneyama et al., 1976) with NOAEL = 85 mg/kg bw, based on histological changes seen in the kidney. In view of the available information it is not possible to determine which single study among those is the most reliable or appropriate for the determination of a NOAEL. Therefore, based on the data from all the studies, a NOAEL of 85 mg/kg bw is proposed, which was derived from a 9- month oral study and corresponds to the NOAEL, which is closest to the lowest available oral LOAEL of 115 mg/kg bw.The NOAELs observed in the repeated dose studies with HCl MIPA (28 days) and DIPA (90 days) were 300 and 100 mg/kg bw, respectively. In the 28 day study anemic effects were seen in male animals. In the 90 day study with DIPA, absolute and relative kidney weights were significantly increased; nonetheless, these kidney effects were not accompanied by any histological changes in the kidney, in the whole dosing regimen. It can therefore be stated that the two substance, LAS Na and DIPA, although they both give rise to effects on the kidney, the observed effects suggest different mechanisms and modes of action. Consequently, their is no need to derive an NOAEL based on considerations of combination toxicity - the lowest NOAEL observed, since NOAELs presuppose absence of effects, is protective for all MoAs.  On this basis, the NOAEL of 85 mg/kg bw for Las Na, is also a safe level for LAS MIPA. The same holds for the anemic effects observed in the study with HCl MIPA, at a much higher dose level of 300 mg/kg bw (NOAEL: 300 mg/kg bw). Based on this reasoning the NOAEL= 85 mg/kg bw/day from the oral repeated-dose (9 months) toxicity study with LAS Na was used for the derivation of a long-term DNEL for LAS MIPA.

The oral NOAEL for LAS MIPA was calculated by scaling based on the molecular weight of the substance: oral NOAEL LAS MIPA = 97.75 mg/kg bw.

Assessment factors used:

Allometric scaling (rat):             4     

Intraspecies (gen. popul.):         5   

Residual interspecies:                2.5  

Sub-chronic to chronic:            2    

AF total:                                  200

This results in an oral DNEL_long-term= 0.49 mg/kg bw for general population.

The oral NOAEL of LAS MIPA for rats (97.75 mg/kg bw) was used in order to extrapolate to a dermal NOAEL. There is no available information on the dermal absorption of LAS MIPA or MIPA, and hence, an 100% dermal absorption was assumed and used for the route-to-route extrapolation for systemic effects. ECHA’s guidance Dose [concentration]-response regarding human health R.8.4.2 pag. 25 states that "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":

dermal NOAEL = oral NOAEL * ABSoral-rat/ABSoral-human <=> corrected dermal NOAEL= 97.75* (1/1) = 97.75 mg/kg bw. The same assessment factors as for the derivation of the oral DNEL were applied. This results in a dermal DNEL_long-term= 0.49 mg/kg bw for general population.

Since no inhalation data are available, cause it not the most relevant exposure route, an inhalation DNEL was also derived on a route-to route extrapolation basis. 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 MIPA or MIPA 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/sRV_rat) * (ABS_oral-rat/ ABS_inh-human) <=> corrected inhalation NOAEL = 97.75 * (1/1.15) * (1/2) = 42.5 mg/m³, where ABS: Absorption; sRV: standard Respiratory Volume; wRV: worker 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. The overall assessment factor is 50.

This results in an inhalation DNEL_long-term= 0.85 mg/m³for the general public.

 

LAS MIPA is not mutagenic and is not considered carcinogenic for humans.Based on the available data, LAS MIPA is not considered a reproductive and developmental toxicant. No DNELs were established.