Reaction mass of disodium [2,2'-(imino-kappaN)dibutanedioato-kappa2O1,O4(4-)]manganese(2-) and sodium sulphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Explanation for the modification of the dose descriptor starting point:

Not applicable (8-hour TWA limit of 5 mg/m³ set by OSHA for general industry for manganese compounds and dusts is used as DNEL for Mn(2Na)IDHA).

AF for dose response relationship:

1

Justification:

8-hour TWA limit is used

AF for differences in duration of exposure:

1

Justification:

8-hour TWA limit is used

AF for interspecies differences (allometric scaling):

1

Justification:

8-hour TWA limit is used

AF for other interspecies differences:

1

Justification:

8-hour TWA limit is used

AF for intraspecies differences:

1

Justification:

8-hour TWA limit is used

AF for the quality of the whole database:

1

Justification:

8-hour TWA limit is used

AF for remaining uncertainties:

1

Justification:

8-hour TWA limit is used

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:

10.1 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):

1

Modified dose descriptor starting point:

other: equivalent interim guidance value

Value:

1.008 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL was derived using interim guidance value of 0.16 mg/kg bw, available for manganese which was converted to an equivalent dose for Mn(2Na)IDHA.

AF for dose response relationship:

1

Justification:

Interim guidance value is used

AF for differences in duration of exposure:

1

Justification:

Interim guidance value is used

AF for interspecies differences (allometric scaling):

1

Justification:

Interim guidance value is used

AF for other interspecies differences:

1

Justification:

Interim guidance value is used

AF for intraspecies differences:

1

Justification:

Interim guidance value is used

AF for the quality of the whole database:

1

Justification:

Interim guidance value is used

AF for remaining uncertainties:

1

Justification:

Interim guidance value is used

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:

The target substance Mn(2Na)IDHA is not acutely toxic by oral and dermal routes of exposure (LD50 > 2000 mg/kg bw; Gruszka, 2007; Kropidlo, 2013). Inhalation is not relevant route of exposure due to the low vapour pressure of the substance (3.36 x 10-5 Pa at 20 °C). The target substance is non-volatile (in microgranulated form) and therefore no risk of irritation or sensitisation of respiratory tract exists. Therefore, no DNELs for acute/short-term exposures (systemic and local effects) and for long-term exposures (local effects for both inhalation and dermal routes) need to be derived.

For the long-term exposure – systemic effects (inhalation and dermal DNEL), the NOAEL of 500 mg/kg bw established in the Combined repeated dose toxicity study with reproduction/ developmental toxicity screening test in rats (Wolterbeek, 2010) was used as the starting point. This is the lowest NOAEL known for the read-across substance Mn(2Na)EDTA after repeated exposures to rats. However, NOAEL of 500 mg/kg bw established for Mn(2Na)EDTA may underestimate the risk of Mn(2Na)IDHA due to the higher absorption of IDHA (37 %) comparing to the absorption of EDTA ligand (5 %) or its complexes (less than 1 -2 %).

The effects in animals treated by imminodisuccinic acid, sodium salt (28-day study, Stropp and Popp, 1997) were less pronounced than those in the Combined study with Mn(2Na)EDTA. The only findings were reduced motor activity in males in the highest dose group. NOAEL was 1000 mg/kg bw for females and 200 mg/kg bw for males. On the other hand, the lowest NOAEL of 5.6 mg Mn/kg bw /day in rats was reported in a maze test (Shukakidze et al. 2003, cited in ATSDR, 2012; please refer to the endpoint summary section “Repeated dose toxicity”). These data allow to speculate that systemic toxicity of Mn(2Na)IDHA will be driven by manganese which systemically available amount is expected to be higher than the amount of Mn(2Na)EDTA. Therefore DNEL derived from the NOAEL for Mn(2Na)EDTA will underestimate the risk of manganese toxicity because Mn(2Na)EDTA is expected to be absorbed less extensively. Therefore, existed safety exposure limits for manganese have been taken to derive an equivalent levels for Mn(2Na)IDHA and compare them with the derived DNELs by classic way by read-across and to make a decision for the most appropriate DNELs for Mn(2Na)IDHA.

The DNELs for inhalation and dermal routes can be derived by route-to-route extrapolation applying appropriate assessment factors.

For the other non-threshold endpoints (mutagenicity, eye and skin irritation/corrosion) no DNELs can be derived because a No-Observed-Effect-Level could not be established from the relevant studies.

Modification of the starting point:

From all available data on the target and read-across substances it is clear that these substances exert their effects by a threshold mode of action. Thus, DNELs can be calculated for the 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 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 (please see below).

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:

The complex Mn(2Na)IDHA is expected to be in de-chelated form in the stomach due to its dissociation under high acidic conditions (for the detailed information on absorption please refer to section "Toxicokinetics, metabolism and distribution" of this CSR or section 7.1 of IUCLID file). Therefore oral absorption will result from released sodium and manganese ions, and free IDHA. Metal ions will be extensively absorbed in the GI tract. The amount of manganese absorbed across the gastrointestinal tract in humans is variable, but typically averages about 3–5 % (SCOEL, 2011). In the toxicokinetic study, the chelating agent IDHA was extensively absorbed and at least 37 % of the administered dose became systemically available in rats (Koester, 2007; Report No. M81819180). Based on this information and taking into account molecular weight of 346.1 g/mol and the negative logPow (-2.69), moderate absorption potential via oral route is expected for Mn(2Na)IDHA. For the purposes of hazard assessment (DNEL derivation), the oral absorption for Mn(2Na)IDHA is set to 50 %, which covers also 37% absorption for free IDHA (worst-case).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 target substance. The log Pow of -2.69 is below the optimal logPow range (0 - 4) values favourable for dermal absorption. High water solubility of 491 g/L points also to a low absorption potential through the skin. The molecular weight of 346.1 g/mol indicates that a certain potential to penetrate the skin (< 500) exists. However, in case of such a hydrophilic substance dermal penetration is rather unlikely. The target substance could dissociate in contact with skin and therefore breakdown products with a slightly deviating absorption pattern are expected. In case of dissociated complexes, manganese ions uptake across intact skin would be expected to be extremely limited (ATSDR, 2012). Low absorption potential through the skin would also apply to free IDHA chelating agent due to its high hydrophilicity (water solubility of 564 g/L; data for Baypure CX 100 (Lanxess, 2014)). Based on these data, dermal absorption is considered to be negligible and equal to 10 % (worst-case) as established for substances which meet criteria of low dermal absorption potential mentioned in ECHA guidance R7c. (the value used for hazard assessment: DNEL derivation). Dermal absorption in rats and in humans is assumed to be the same since no information for dermal absorption of the target substance in humans is available.

Inhalation absorption

Absorption by inhalation is considered to be negligible due to the low vapour pressure of 3.36 x 10-5 Pa at 20 °C and that the substance is in microgranulated form with particles with aerodynamic diameter higher than 100 µm. It means that 100 % of inhaled substance (in case of dust forming) will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, 50% will be absorbed in the GI tract and become systemic available: 1 x 0.5 = 0.5 will be the total absorption factor for inhalation (or 50%). Absorption by inhalation is 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/sRV rat) x (ABS oral-rat/ABS inh-human) x (6.7 m³/10 m³) where sRV is the 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 dermal NOAEL for systemic effects. The following formula was used (as described in the Example B.5 of the Appendix R.8 -2, ECHA REACH Guidance R8):

Corrected dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS derm-rat) x (ABS derm-rat/ABS derm-human) = oral NOAEL x (ABS oral-rat/ABS derm-human).

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 (0.38 m³).

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the 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 Combined oral repeated dose toxicity study with reproduction/ developmental toxicity screening study in rats, which was used to derive the dermal long-term DNEL.

No allometric scaling factor was applied when the oral NOAEL 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 (Combined screening study = sub-chronic).

Quality of whole data base:

A default assessment factor of 1 was used.

Issues related to dose response:

An assessment factor of 1 was applied when the NOAEL from the Combined study was extrapolated to NOAEL (clear dose-response was observed).

Calculation of DNELs:

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

The oral rat NOAEL of 500 mg/kg bw (established for the read-across substance Mn(2Na)EDTA) 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 %/50 %) x (6.7/10) = 881.6 mg/m³

DNEL = 881.6 mg/m³/(2.5 x 5 x 2 x 1 x 1) = 35.3 mg/m³.

Assessment factors are: 2.5 – remaining interspecies differences, 5 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 25.

There is IOELV of 0.05 mg/m³ for respirable fraction for manganese and its inorganic compounds available (SCOEL, 2011; ATSDR, 2012). Since no respirable fraction is expected for Mn(2Na)IDHA (particles of Mn(2Na)IDHA are > 100 µm), an IOELV of 0.2 mg/m³ for inhalable fraction would be more appropriate. This limit would correspond to 1.26 mg/m³ of Mn(2Na)IDHA: ((MW of Mn(2Na)IDHA 346.08 g/mol/ MW of manganese 54.94 g/mol) x 0.2 mg/m³). Taking into account 50 % absorption by inhalation (equal to oral absorption), the estimated NOAEC (=DNEL for inhalation, systemic effects) would result in 2.52 mg/m³: 1.26 x (100 %/50 %).

The estimated concentration of 2.52 mg/m³ is of the same order of magnitude as the limit of 5 mg/m³ (8-hour TWA) set by OSHA for general industry for manganese compounds and dusts.

This equivalent concentration of 2.52 mg/m³ calculated for Mn(2Na)IDHA is lower than the derived DNEL of 35.3 mg/m³ based on NOAEL for the read-across substance Mn(2Na)EDTA. Therefore, the DNEL of 35.3 mg/m³ may underestimate the risk originating from the toxicity of manganese due to Mn(2Na)IDHA exposure. The equivalent concentration of 2.52 mg/m³ may however overestimate the risk because it is based on IOELV for inorganic compounds which dissociation scheme is different from the dissociation of inner sphere of metallocomplexes.

Based in these data and due to the absence of specific toxicity data for long-term exposure by inhalation for Mn(2Na)IDHA, 8-hour TWA limit of 5 mg/m³ set by OSHA for general industry for manganese compounds and dusts will be appropriate for Mn(2Na)IDHA.

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 derm-human) = 500 x (50 %/10 %) = 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 (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 100.

Based on the interim guidance value of 0.16 mg/kg bw, available for manganese (ATSDR, 2012) an equivalent dose for Mn(2Na)IDHA for systemic effects for humans can be estimated (please refer to the endpoint summary section “Repeated dose toxicity”). It corresponds to 1.008 mg/kg bw for Mn(2Na)IDHA: ((MW of Mn(2Na)IDHA is 346.08 g/mol/ MW of Mn is 54.94 g/mol) x 0.16 mg/kg bw). This dose level however may be overprotective but it can serve as an internal DNEL for systemic effects.

Taking into account absorption rate of 10% for dermal route, when 1.008 mg/kg bw corresponds to 10% absorbed through the skin, then 1.008 x 100/10 = 10.1 mg/kg bw corresponds to an external dermal dose. 10.1 mg/kg bw < 25 mg/kg bw derived using read-across NOAEL.

Selected DNELs

DNEL systemic inhalation = 5 mg/m³

DNEL systemic dermal (long-term) = 10.1 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.52 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1

Explanation for the modification of the dose descriptor starting point:

Not applicable (DNEL is derived based on IOELV of 0.2 mg/m³ for inhalable fraction for manganese and its inorganic compounds)

AF for dose response relationship:

1

Justification:

IOELV is used

AF for differences in duration of exposure:

1

Justification:

IOELV is used

AF for interspecies differences (allometric scaling):

1

Justification:

IOELV is used

AF for other interspecies differences:

1

Justification:

IOELV is used

AF for intraspecies differences:

1

Justification:

IOELV is used

AF for the quality of the whole database:

1

Justification:

IOELV is used

AF for remaining uncertainties:

1

Justification:

IOELV is used

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:

10.1 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):

1

Modified dose descriptor starting point:

other: Interim guidance value

Value:

1.008 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

DNEL was derived using interim guidance value of 0.16 mg/kg bw, available for manganese which was converted to an equivalent dose for Mn(2Na)IDHA.

AF for dose response relationship:

1

Justification:

Interim guidance value is used

AF for differences in duration of exposure:

1

Justification:

Interim guidance value is used

AF for interspecies differences (allometric scaling):

1

Justification:

Interim guidance value is used

AF for other interspecies differences:

1

Justification:

Interim guidance value is used

AF for intraspecies differences:

1

Justification:

Interim guidance value is used

AF for the quality of the whole database:

1

Justification:

Interim guidance value is used

AF for remaining uncertainties:

1

Justification:

Interim guidance value is used

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:

1.008 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):

1

Modified dose descriptor starting point:

other: equivalent interim guidance value

Value:

1.008 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable (DNEL was derived using interim guidance value 0.16 mg/kg bw, available for manganese which was converted to an equivalent dose for Mn(2Na)IDHA).

AF for dose response relationship:

1

Justification:

Interim guidance value is used

AF for differences in duration of exposure:

1

Justification:

Interim guidance value is used

AF for interspecies differences (allometric scaling):

1

Justification:

Interim guidance value is used

AF for other interspecies differences:

1

Justification:

Interim guidance value is used

AF for intraspecies differences:

1

Justification:

Interim guidance value is used

AF for the quality of the whole database:

1

Justification:

Interim guidance value is used

AF for remaining uncertainties:

1

Justification:

Interim guidance value is used

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 by oral route)

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.

 

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 (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) = 500 mg/kg bw x (1/1.15 m³/kg/day) x (50%/50%) = 434.8 mg/m³

DNEL = 434.8 mg/m³/(2.5 x 10 x 2 x 1 x 1) = 8.7 mg/m³. Assessment factors are: 2.5 – remaining interspecies differences, 10 – intraspecies, 2 – study duration (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 50.

However, the equivalent concentration of 2.52 mg Mn(2Na)IDHA /m³ calculated from the IOELV for manganese (see above) is < 8.7 mg/m³ (DNEL based on NOAEL from the read-across substance Mn(2Na)EDTA) is more appropriate for general public. It is lower than 8-hour TWA of 5 mg/m³ for general industry for manganese compounds and dusts.

 

Long-term exposure – systemic effects (dermal DNEL)

Dermal NOAEL =oral NOAEL x (ABS oral-rat/ABS derm-human) = 500 x (50 %/10 %) = 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 (sub-chronic study), 1 – dose response, 1 – quality of data base. The total AF amounts to 200.

As in case with workers, the dose of 10.1 mg Mn(2Na)IDHA /kg bw equivalent to interim guidance value of 0.16 mg/kg bw available for manganese (see above) is < 12.5 mg/kg bw (based on NOAEL from the read-across substance Mn(2Na)EDTA) and therefore is more appropriate as DNEL.

 

Long-term exposure – systemic effects (oral DNEL)

The oral NOAEL of 500 mg/kg bw does not need to be modified into a corrected NOAEL since no difference in oral absorption between animals and humans are considered (example A.1 in ECHA Guidance R.8):

Corrected oral NOAEL = oral NOAEL x (ABS oral-rat/ABS oral-human) = 500 mg/kg bw x (50%/50%) = 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 (sub-chronic study), 1 – dose response (NOAEL is used), 1 – quality of data base (default). The total AF amounts to 200.

Interim guidance value of 0.16 mg/kg bw, available for manganese is equivalent to 1.008 mg/kg bw for Mn(2Na)IDHA: ((MW of Mn(2Na)IDHA is 346.08 g/mol/ MW of Mn is 54.94 g/mol) x 0.16 mg/kg bw) (please refer to the endpoint summary section “Repeated dose toxicity”). This dose is lower than 2.5 mg/kg bw calculated from the NOAEL of 500 mg/kg bw for the read-across substance Mn(2Na)EDTA. The value of 1.008 mg/kg bw may however be overprotective for Mn(2Na)IDHA but in the absence of substance specific long-term toxicity data, it can serve as internal DNEL.

Selected DNELs

DNEL systemic inhalation = 2.52 mg/m³

DNEL systemic dermal (long-term) = 10.1 mg/kg bw

DNEL systemic oral (long-term) = 1.008 mg/kg bw