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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.63 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
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
440.79 mg/m³
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/0.38 m3/kg/d and the absorption rates for Absorption (oral 50 %, inhalation 100 %) and the standard respiratory volume in humans/ worker respiratory volume (6.7 m3 (8 h) / 10 m3 (8 h)).

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
25 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
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004). This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %).

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default factor for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

For magnesium sulfonate target substance, the following dose descriptors are available:

Acute/short-term exposure – systemic effects (dermal DNEL):

There are no acute studies available for the test substance. However, there are acute oral studies in rats available for the magnesium and calcium sulfonate read across substances (CAS 71786-47-5 - Sanitised, A., 1980, CAS 70024-69-0 - Swan, 1972, Analogue of CAS 70024-69-0 - Sanitised, D:, 1989 and CAS 115733-09-0 - Sanitised, B., 1981). The calcium read across substances (Analogue of CAS 70024 -69 -0 and CAS 115733-09-0) were also tested in dermal irritation studies in rats or rabbits (Sanitised, E., 1989 and Sanitised, C., 1981). The results show that the read across substances are non-toxic by ingestion and by skin contact; no remarkable systemic toxicity is reported. Oral LD50 values of > 16,000, LD50 >10,000 - < 20,000 and LD50 > 5,000 mg/kg bw/day were reported.

Since the read across substances are not acutely toxic and this behaviour is also expected for the target substance, no DNEL for acute systemic effects needs to be derived. The DNEL for acute systemic effects by the dermal route is unnecessary since the long-term DNEL covers sufficiently the risk of short-term exposure.

Acute/short-term exposure – systemic effects (inhalation DNEL):

No acute inhalation study is available. However, the magnesium sulfonate target substance is not expected to pose an inhalation hazard due to its low vapour pressure (1.0E-2 Pa at 25 °C). Therefore, no DNEL is required.

Acute/short-term exposure – local effects (dermal DNEL):

The substance magnesium sulfonate target substance is not irritating to the skin of rabbits after 4-hour application of test material (Kerr, 1999). LD50 values above 2,000 were reported for the read across substances in the dermal studies. Thus, the short-term dermal DNEL needs not to be derived and is sufficiently covered by the long-term DNEL for systemic and local effects.

Acute/short-term exposure – local effects (inhalation DNEL):

The magnesium sulfonate target substance does not pose an airborne hazard, due to its low vapour pressure. The long-term inhalation DNEL for systemic effects covers sufficiently local effects.

Long-term exposure – systemic effects (dermal DNEL):

No repeated dose data is available for the target substance. However the long-term systemic DNEL for the dermal route has been derived from the NOAEL of an oral subchronic one-generation reproductive toxicity study in rats with the calcium sulfonate read across substance, (CAS 115733 -09 -0, Bjorn, 2004). A NOAEL of 500 mg/kg bw/day was established. The starting point for the DNEL derivation is the oral NOAEL (route-to-route extrapolation necessary).

Long-term exposure – systemic effects (inhalation DNEL):

There are no dose-response and route-specific information on repeated dose toxicity via inhalation. The substance does not pose a hazard for humans by the inhalation route of exposure. The inhalation DNEL can be derived from the oral NOAEL of 500 mg/kg bw established in the oral one-generation study in rats (Bjorn, 2004) by route-to-route extrapolation.

Long-term exposure – local effects (dermal DNEL):

No long-term dermal DNEL for local effects is derived because the magnesium sulfonate target substance is not irritating to the skin and the systemic dermal DNEL is sufficient to cover local effects.

Long-term exposure – local effects (inhalation DNEL):

No long-term inhalation DNEL for local effects is needed since the magnesium sulfonate target substance is not expected to be irritating or sensitizing to respiratory system. Local effects are covered sufficiently by the long-term DNEL for systemic effects.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because no No-Observed-Effect-Level could be established from the relevant studies. However there does not exist any hazard as no classification of the magnesium sulfonate target substance was necessary.

 

Modification of the starting point:

From all available data on the magnesium sulfonate target substance, (CAS 231297-75-9), and on the magnesium and calcium sulfonate read across substances for the different human health endpoints, it is clear that the substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the target substance and for the read across substances, reflecting the routes, the duration and the frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

Bioavailability (absorption):

There is no substance-specific experimental information on absorption by the oral, dermal and inhalation routes available. The absorption rates are assessed based on the physico-chemical properties and on the effects observed in treated animals in the available studies.

Oral absorption:

Due to the molecular weight of 955.8 g/mol, a logPow of > 6.4 (predicted LogPow for the undissociated substance is 21.8) together with the non-irritating properties of the substance and the very slight effects found at the highest dose level in the subacute study in rats, absorption via the oral route is considered to be slight to moderate for the target substance (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). The oral absorption is set to 50% since physico-chemical properties of the substance are not in range suggestive of significant absorption from the gastro-intestinal tract. The oral absorption is considered to be the same in animals and in humans (worst-case).

Dermal absorption:

No significant dermal absorption is expected for the magnesium sulfonate target substance. The log Pow of > 6.4, the water solubility of 0.198 mg/L and the molecular weight of 955.8 point to a poor absorption through the skin. According to the TGD, Part I, Appendix IV, 10% of dermal absorption can be considered in this case, since the criteria for molecular weight and Log Pow are met (MW above 500 g/mol and log Pow > 4). Moreover, a critical assessment of all available data (toxicity effects in the available studies and physicochemical properties) should be taken into account before using default assumptions (ECETOC, TR No. 110). The absorption after dermal exposure is generally more gradual and slower than oral absorption and a lower bioavailability is expected due to the presence of the absorption hindering outer skin layer stratum corneum and a comparatively smaller surface area. Schuhmacher et al. recommended that a low dermal penetration (< 10%) can be assumed for substances with a logPow value >5 or for substances with a Kp value <0.0001 (cm/h). (Schumacher et al., 2003). A skin permeability constant (Kp) of 1.0E-7 cm/min (= 6.0E-6 cm/h) for human epidermis was obtained experimentally for the related substance dodecyl benzenesulfonate (CAS 25155-30-0, Howes, 1975). This substance is structurally similar to the magnesium sulfonate target substance, but its alkyl chain consisting of 12 carbon atoms is shorter and therefore it is less lipophilic. The Kp value for the magnesium sulfonate target substance, which is even more lipophilic than dodecyl benzenesulfonate, is expected to be much lower. Thus, 10% absorption applies also in this case.

 

Dermal absorption in rats, rabbits and in humans is assumed to be the same since no information for dermal absorption of the magnesium sulfonate target substance in humans is available.

 

Reference:

1.      Schuhmacher-Wolz U., Kalberlach F., Oppl R., van Hemmen J.J. (2003). A toolkit for dermal risk assessment: toxicological approach for hazard characterization. Ann. Occup. Hyg., Vol 47 No.8, pp. 641 -652.

 

Inhalation absorption

Absorption by inhalation is considered to be negligible (low vapour pressure of 1.0E-2 Pa at 25°C) and not to be higher than absorption by oral route. However, 100% absorption is assumed for inhalation route and considered to be equal in rats and in humans since no substance specific information is available.

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to obtain long-term inhalation NOAEC for systemic effects. The following formula was used:
corrected inhalatory NOAEC = oral NOAEL x (1/sRVrat) x (ABSoral-rat/ABSinh-human) x (6.7 m³/10 m³) where sRV is standard respiratory volume of rats during 8 hours (= 0.38 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity.

Oral-to-dermal extrapolation is performed to obtain long-term dermal NOAEL for systemic effects. The following formula was used: corrected dermal NOAEL = oral NOAEL * (ABS oral-rat/ABS dermal-rat) * (ABS dermal-rat/ ABSs dermal-human), where ABS is absorption.

Exposure conditions:

No modification of the starting points for exposure conditions was necessary since the systemic dose after oral administration of the test material was already assessed in respiratory volume taken for rats during 8 h (0.38m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the subchronic oral one-generation reproductive toxicity study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

Applying of assessment factors and calculation of DNELs:

The assessment factors have been applied to the corrected starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAEL from the subchronic one-generation reproductive toxicity study, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL from the one-generation study was used for the derivation of inhalation long-term DNEL. An assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

Intraspecies differences:

An assessment factor of 5 was applied for workers for all endpoints and for all exposure routes..

Extrapolation of duration:

An assessment factor of 2 was applied for duration of exposure (subchronic study).

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

A default assessment factor of 1 was applied when the NOAEL from the subchronic oral one-generation reproductive toxicity study was used.

 

Calculation of DNELs:

Long-term exposure – systemic effects (dermal DNEL):

For the oral rat NOAEL of 500 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 2500 mg/kg bw

DNEL = 2500 mg/kg bw/(4 x 2.5 x 5 x 2 x 1 x 1) = 25 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 100.

Long-term exposure – systemic effects (inhalation DNEL):

The oral rat NOAEL of 500 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 500 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7/10) = 440.79 mg/m³

DNEL = 440.79 mg/m³/(2.5 x 5 x 2 x 1 x 1) = 17.63 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 25.

 

Selected DNELs

DNEL systemic dermal = 25 mg/kg bw

DNEL systemic inhalation = 17.63 mg/m³

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.35 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
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
217.39 mg/m³
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 500 mg/kg bw /day from an oral one-generation toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0) is available (Bjorn, 2004). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/1.15 m3/kg/d for a 24-hour exposure and the absorption rates (oral 50 %, inhalation 100 %).

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling should be applied in case of dermal-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.5 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
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 500 mg/kg bw /day from the one-generation oral repeated dose toxicity study with the calcium sulfonate read across substance, (CAS 115733-09-0), is available for rats (Bjorn, 2004). This value was converted into the corrected dermal NOAEL taking into account the rates for absorption (oral 50 %, dermal 10 %).

AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-4 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default factor for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
2.5 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
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not relevant
AF for dose response relationship:
1
Justification:
default (three doses were tested, using a spacing range of 2-5 fold)
AF for differences in duration of exposure:
2
Justification:
since it is a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default for rats
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
default
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties are identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

Modification of the starting point:

Bioavalability (absorption):

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.15 m³/kg bw for rats was used to convert dermal NOAEL into inhalation NOAEC.

Applying of assessment factors:

A higher assessment factor of 10 (in place of 5 for workers) for intraspecies variation/differences of human population was used.

Calculation of endpoint-specific DNEL for general population

Long-term exposure - systemic effects (oral):

The oral NOAEL of 500 mg/kg bw had not to be converted.

The oral NOAEL of 500 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available: Oral NOAEL rat = oral NOAEL human = 500 mg/kg bw.

DNEL = 500 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 2.5 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 200.

Long-term exposure - systemic effects (dermal):

For the oral rat NOAEL of 500 mg/kg bw the following conversion was necessary:

dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-rat) x (ABS dermal-rat/ABS dermal-human) = 2500 mg/kg bw

DNEL = 2500 mg/kg bw/(4 x 2.5 x 10 x 2 x 1 x 1) = 12.5 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (subchronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 200.

Long-term exposure - systemic effects (inhalation):

The oral NOAEL of 500 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABS oral-rat/ABS inhal-human),where 1.15 is the standard respiratory volume (m³/kg bw) of rats during 24 h exposure, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 500 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 217.39 mg/m³

DNEL = 217.39 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 4.35 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default). The total AF amounts to 50.

Selected DNELs

DNEL systemic oral = 2.5 mg/kg bw

DNEL systemic dermal = 12.5 mg/kg bw

DNEL systemic inhalation = 4.35 mg/m³