Sodium 3-mercaptopropanesulphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.342 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:

308.55 mg/m³

Explanation for the modification of the dose descriptor starting point:

A NOAEL of 350 mg/kg bw /day from a chronic oral repeated dose toxicity study with the read across substance CAS 19767-45-4 is available (Toolbox-Prediction, Chemservice S.A., 2012). 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 (dermal 50 %, worst case - 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

AF for differences in duration of exposure:

1

Justification:

since it is a chronic 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:

2

Justification:

remaining uncertainties due to use of read across

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:

3.5 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):

100

Modified dose descriptor starting point:

NOAEL

Value:

350 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long-term systemic DNEL for the dermal route has been derived from the NOAEL of 350 mg/kg bw established in the oral chronic study in rats with mesna - CAS 19767-45-4 (Chemservice S.A., 2012). As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and is also expected to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

since it is a chronic 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:

2

Justification:

remaining uncertainties due to use of read across

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

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 1-Propanesulfonic acid, 3-mercapto-, monosodium salt, DNELs are needed for chronic exposure by the oral (only for consumers), dermal (for workers and consumers) and inhalation routes of exposure (workers and consumers). Inhalation is not a relevant route of exposure due to the low vapour pressure of the substance. Since 1-Propanesulfonic acid, 3-mercapto-, monosodium salt does not represent an acute hazard (not classified for acute toxicity), no DNELS for acute systemic toxicity need to be derived.

No DNELs are needed for local effects because there is no dose-response and route-specific information on these endpoints. Long-term systemic DNELs cover sufficiently local effects.

From all available data for the different human health endpoints it is clear that 1-Propanesulfonic acid, 3-mercapto-, monosodium salt exerts its effect 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 related substances, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment.

There are following annotations for each endpoint:

- Since the substance is not acutely toxic by the dermal route of exposure, no acute DNEL needs to be derived. This is based on a LD50 greater than 2000 mg/kg bw (as evident from all weight of evidence pieces).

- Acute DNELs for inhalation (systemic and local) are not necessary since there is no acute toxic hazard by inhalation.

- A qualitative approach in hazard assessment for eye and skin irritation/corrosion and skin sensitisation is used because no dose descriptors are available on these endpoints.

- For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.

- There is no animal data on repeated oral, dermal or inhalation exposure. To cover this endpoint, data from an oral gavage chronic study in rats with the read across substance mesna - CAS 19767-45-4 (Toolbox-Prediction, Chemservice S.A. 2012) has been used to calculate the long-term DNELs.

-No DNELs for reprotoxic effects are derived because the Toolbox-Predictions indicate no reproductive hazard arising from analogue substances of 1 -Propanesulfonic acid, 3 -mercapto-, monosodium salt. Therefore the substance is not expected to be reprotoxic and the hazard is covered sufficiently by the systemic long-term DNELs.

First of all, available dose descriptors were converted into a corrected starting point to take into account differences in routes of exposure between experimental animals and humans and differences in human and animal exposure conditions. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

The assessment factors are applied in accordance with the recent ECHA guidance document and the ECETOC Technical Report No. 110, October 2010.

Modification of the relevant dose descriptors to the correct starting point:

Bioavailability (absorption)

50% of dermal absorption is considered for the target substance. The dermal absorption in rats and in humans is assumed to be the same since no experimentally determined values for dermal absorption of the target chemical in rats and in humans are available. In case of oral to inhalation extrapolation, 50% absorption is assumed for oral absorption in rats and 100% absorption for inhalation is assumed in humans (worst case; according to the ECETOC Report No 110, 100% absorption for inhalation can be used in case of absence of substance specific data for absorption).

Route-to-route extrapolation:

Oral-to-inhalation extrapolation is performed to assess long-term inhalation effects in humans. In addition, oral-to-dermal extrapolations are conducted to assess long-term dermal effects in humans.

Exposure conditions:

Exposure time differed in workers and in the chronic oral study in rat with the read across substance mesna (CAS 19767-45-4). Rats were exposed to the test substance once daily via gavage, while workers are exposed 8h daily (5days/week). 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 hours (0.38m³) (see formula of modification of the starting point by oral-to-inhalation extrapolation.

Respiratory volumes:

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the chronic gavage study in rats with mesna (CAS 19767 -45 -4) 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:

Interspecies differences:

The species-specific default assessment factor of 4 for allometric scaling for rats is applied in case of usage of oral NOAEL to derive dermal DNEL.

No allometric scaling factor is applied in case of oral-to-inhalation extrapolation.

An additional assessment factor of 2.5 is applied for remaining interspecies differences in toxicodynamics between rats and humans.

 

Intraspecies differences: 

Assessment factor of 5 is applied for workers for all endpoints and for all exposure routes. The factor of 10 is used in the process of DNEL-calculation for general population.

Extrapolation of duration:

An assessment factor of 1 was applied in case of the chronic oral repeated dose toxicity study with mesna (CAS 19767-45-4) as no extrapolation is needed.

 

Quality of whole data base:

An assessment factor for uncertainties in the quality of the data base is regarded to be 1, as all studies used to derive the DNELs were GLP-guideline studies..

 

Issues related to dose response:

Assessment factor of 1 was used.

Remaining uncertainties:

As the DNELs are based on a study performed with the read across substance mesna (CAS: 19767-45-4), an additional assessment factor of 2 was used for the remaining uncertainties.

Calculation of endpoint-specific DNELs for workers

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 350 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 350 mg/kg bw x (50%/50%) = 350 mg/kg bw.

DNEL = 350 mg/kg bw/(4 x 2.5 x 5 x 1 x 1 x 1 x 2) = 3.5 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default), 2 - remaining uncertainties (due to read-across).

Long-term exposure - systemic effects (inhalation)

The oral NOAEL of 350 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) = 350 mg/kg bw x (1/0.38 m³/kg/day) x (50%/100%) x (6.7/10) = 308.55 mg/m³

DNEL = 308.55 mg/m³/(2.5 x 5 x 1 x 1 x 1 x 2) = 12.342 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration (chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default) 2 - remaining uncertainties (due to read across).

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.04 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:

152.174 mg/m³

Explanation for the modification of the dose descriptor starting point:

A NOAEL of 350 mg/kg bw /day from a chronic oral repeated dose toxicity study with the read across substance CAS 19767-45-4 is available (Toolbox-Prediction, Chemservice S.A., 2012). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory volume of rats of 1/1.15 m3/kg/d and the absorption rates for Absorption (dermal 50 %, worst case - inhalation 100 %).

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

since it is a chronic 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:

10

Justification:

default for consumers

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

2

Justification:

remaining uncertainties due to use of read across

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:

1.75 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:

350 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long-term systemic DNEL for dermal route has been derived from the NOAEL of 350 mg/kg bw established in the oral chronic study in rats with mesna - CAS 19767-45-4 (Chemservice S.A., 2012). As seen in the acute dermal study in rats, the substance was not systemically toxic by the dermal route and is also expected to be of lower systemic toxicity after prolonged exposure with the skin. The starting point for the DNEL derivation can be obtained by conversion of oral NOAEL into dermal NOAEL (route-to-route extrapolation).

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

since it is a chronic 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 consumers

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

2

Justification:

remaining uncertainties due to use of read across

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:

1.75 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:

350 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long-term systemic DNEL for oral route has been derived from the NOAEL of 350 mg/kg bw established in the oral chronic study in rats with mesna - CAS 19767-45-4 (Chemservice S.A., 2012).

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

since it is a chronic 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 consumers

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

2

Justification:

remaining uncertainties due to use of read across

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:

Bioavailability (absorption)

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

Respiratory volumes:

- No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account.

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 350 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available.

DNEL = 350 mg/kg bw/(4 x 2.5 x 10 x 1 x 1 x 1 x 2) = 1.75 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default), 2 - remaining uncertainties (due to read-across).

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 350 mg/kg bw was converted into the dermal NOAEL: Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 350 mg/kg bw x (50/50%) = 350 mg/kg bw.

DNEL = 350 mg/kg bw/(4 x 2.5 x 10 x 1 x 1 x 1 x 2) = 1.75 mg/kg bw. Assessment factors are: 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default), 2 - remaining uncertainties (due to read across).

Long-term exposure - systemic effects (inhalation)

The oral NOAEL of 350 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 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 = 350 mg/kg bw x (1/1.15 m³/kg/day) x (50%/100%) = 152.174 mg/m³

DNEL = 152.174 mg/m³/(2.5 x 10 x 1 x 1 x 1 x 2) = 3,04 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (chronic study), 1 – dose response (clear dose response), 1 – quality of data base (default), 2 - remaining uncertainties (due to read-across).