Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.89 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):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
56 mg/m³
Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:
1
Justification:
adequate data available
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.84 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
5
AF for other interspecies differences:
2
AF for intraspecies differences:
1
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.68 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: SCOEL approach
Overall assessment factor (AF):
2
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Justification for read across

The derivation of the DNELs is based on read across to other sulfur based substances. Toxicological data specifically for Sodium sulfide (Na2(Sx)) from animal studies are not available. Therefore, because of the lack of appropriate experimental data, read-across from studies with H2S is proposed based on the following reasoning:

                   

Unrestricted read-across between the substances Sodium sulfide (Na2(Sx)), sodium hydrogensulfide and dihydrogen sulfide is considered feasible, in view of the potential systemic toxicity being driven by the sulfide ion as the only relevant species released from any of the sulfide substances under physiological conditions. In this context, it is further considered to be very unlikely that the sodium ions add any toxicological concern.

 

Aqueous Na2Sx solutions are only stable at pH > 10. At lower pH values they are decomposed to H2S and S ([1, 2, 3, 4, 5])

 

The soluble compound Sodium sulfide (Na2(Sx)) can safely be assumed to be present dissociated in water and relevant biological media([6]). From Sodium sulfide (Na2(Sx)), hydrogen sulfide (H2S) may be formed according to the following equilibria:

Na2Sx+ H2O → NaOH + NaHSx(2 Na++ HSx-+ OH-)

NaHSx +H2O → (x-1)S + NaOH + H2S (Na++ OH-+ H2S)

The toxic effects resulting from the sodium ion is negligible. Hydrogen sulfide dissociates in aqueous solution to form two dissociation states involving the hydrogen sulfide anion and the sulfide anion:

H2S ↔ H++ HS-↔ 2 H++ S2-

The pKa values for the first and second dissociation steps of H2S are 7.04 and 11.96, respectively. Therefore, at physiological pH values, hydrogen sulfide in the non-dissociated form (H2S) and the hydrogen sulfide anion (HS-) will be present in almost equimolar proportion, whereas only very small amounts of the sulfide anion (S2-) will be present. In conclusion, under physiological conditions, inorganic sulfides or hydrogen sulfides as well as H2S will dissociate to the respective species relevant to the pH of the physiological medium, irrespective the nature of the “sulfide”, which is why read-across between these substances and H2S is considered to be feasible without any restrictions.

 

[1] E. Dachselt, „Thioplaste“, Deutscher Verlag für Grundstoffindustrie, Leipzig 1971, pp. 35

[2] M.B. Berenbaum, “Polysulfide Polymers” in N. G. Gaylord, ”Polyethers”, Interscience Publishers, 1962, 49-51

[3] D. Peschanski; G. Valensi, J. chim.Phys. 46(1949), pp. 602

[4] M. Menzel, Expert statement “Investigation of the reaction of sodium polysulfide solution with diluted hydrochlorioc acid”, AkzoNobel, Greiz (March 2010) (attached)

[5] Hagg-graph (attached)

[6] Beauchamp et al. (1984): A critical review of the literature on hydrogen sulfide toxicity; CRC Crit. Rev. Toxicol. 13, 25-97.

 

The long term exposure systemic inhalation DNELis based on the NOAEC derived from the 90-day inhalation study by Dorman et al. (2004) in Fischer 344 rats, Sprague-Dawley rats and B6C3F1 mice. In this study some minor effects were observed on food consumption and body weight. Otherwise no significant or relevant effect were seen in this study. Therefore, the concentration of 80 ppm H2S can be considered as NOAEC for systemic effects.

 

Modification of the dose descriptor to the correct starting point

Conversion of ppm to mg/m3

mg/m3 = (ppm) × (molecular weight of H2S)/(24.45)

mg/m3 = 80 ppm x (34.08/24.45)

mg/m3 = 111.15

NOAEC rat to NOAECCor.

NOAECCor.= NOAEC rat x (6h/d / 8h/d) x (6.7 m3 / 10 m3)

NOAECCor. = 111.15 x (6h/d / 8h/d) x (6.7 m3 / 10 m3)

NOAECCor. = 56 mg/m3

 

DNEL for H2S

Assessment factor

Accounting for

Default values applied

Inter-species variability

-correction for differences in metabolic rate (AS)*

1

-remaining differences (e.g. toxicokinetics/-dynamics)

2.5

Intra-species variability

-workers

5

Exposure duration

-subchronic to chronic

2

Dose response

-adequate data available

1

Quality of whole data base

-no need for a further assessment factor

1

Overall

 

25

DNEL (mg/m3) = NOAECCor./overall AF = 56/25 = 2.24 mg/m3

* not applicable, included the NOAEC rat to NOAECCor, see R8 page 25.

 

DNEL for Na2Sx (x = 1.5-5)

H2S = 34 g/mol = 2.24 mg/m3

S2- = 32 g/mol = 2.10 mg/m3

Na2Sx(x = 1,5-5) = 94.1- 206.35 g/mol

1.5*32 – 5*32 g/mol = 48-160gS2- : 94.1-206.35 g/mol = 0.5100-0.7753 = 51-77.5 % (mass percentage S2- in Na2Sx (x1.5-5)

51-77.5 % = 2.10 mg/m3 > 100 % (Na2Sx (x = 1.5-5))= 4.39 -2.89 mg/m3

Accordingly, a concentration of2.89mg/m3was derived as thelong-term DNEL for systemic effects in

workers exposed via inhalation to Na2Sx (x = 1.5-5)(representing Na2S (x=5) – as a worst-case).

 

The long term exposure local inhalation DNELThe long term exposure local inhalation DNEL is based on a NOAEC derived from the 90-day inhalation study by Dorman et al. (2004) in Fischer 344 rats, Sprague-Dawley rats and B6C3F1 mice. An increased incidence of olfactory neuronal loss (ONL) was observed at 30 and 80 ppm of hydrogen sulfide. Therefore a NOAEC of 10 ppm H2S for local effects was derived.

 

Modification of the dose descriptor to the correct starting point

Conversion of ppm to mg/m3

mg/m3 = (ppm) × (molecular weight of H2S)/(24.45)

mg/m3 = 10 ppm x (34.08/24.45)

mg/m3 = 13.94

NOAEC rat to NOAECCor.

NOAECCor.= NOAEC rat x (6h/d / 8h/d) x (6.7 m3 / 10 m3)

NOAECCor. = 13.94 x (6h/d / 8h/d) x (6.7 m3 / 10 m3)

NOAECCor. = 7 mg/m3

 

DNEL for H2S

Assessment factor

Accounting for

Default values applied

Inter-species variability

-correction for differences in metabolic rate (AS)

1*

-remaining differences (e.g. toxicokinetics/-dynamics)

1*

Intra-species variability

-workers

5

Exposure duration

-subchronic to chronic

2

Dose response

-adequate data available

1

Quality of whole data base

-no need for a further assessment factor

1

Overall

 

10

DNEL (mg/m3) = NOAECCor./overall AF = 7/10 = 0.7 mg/m3

* not applicable, see R8 page 25.

 

DNEL for Na2Sx (x = 1.5-5)

H2S = 34 g/mol = 0.7 mg/m3

S2- = 32g/mol = 0.65 mg/m3

Na2Sx(x = 1,5-5) = 94.1- 206.35 g/mol

1.5*32 – 5*32 g/mol = 48-160gS2- : 94.1-206.35 g/mol = 0.5100-0.7753 = 51-77.5 % (mass percentage S2- in Na2Sx (x1.5-5)

51-77.5 % = 0.65 mg/m3 > 100 % (Na2Sx (x = 1.5-5))= 1.27-0.84 mg/m3

Accordingly, a concentration of0.84mg/m3was derived as thelong-term DNEL for local effects in

workers exposed via inhalation to Na2Sx (x = 1.5-5)(representing Na2S (x=5) – as a worst-case).

  

The long term exposure local inhalation DNEL based on NaOHbecause the second potential mechanism of local toxicity in the respiratory tract can be attributed to the presences of OH- ions formed after the rapid decomposition of sodium sulfide (Na2(Sx) x=1,5-5), a DNEL was also derived for local effects of NaOH, for purposes of comparison:

 

For NaOH aDNEL of 1 mg/m3was derived in the REACH registration dossier for long-term local effects in workers following inhalation exposure.

 

Calculation DNEL forsodium sulfide(Na2(Sx) x=1,5-5)

(i) NaOH = 40 g/mol = 1.00 mg/m3

(ii) OH- = 17 g/mol = 0.425 mg/m3

 

The calculation is based on the following equations for the solution of sodium sulfide (Na2(Sx) x=1,5-5)

in water:

Na2Sx + H2O → NaOH + NaHSx (2Na+ + OH- + HSx-)

NaHSx + H2O → (x-1)S + NaOH + H2S (Na+ + OH- + H2S)

Thus, it is concluded that 1 mol sodium sulfide (Na2(Sx) x=1,5-5) in solution will result in 2 mol OH- (worst-case assuming full conversion).

 

Converted to the unit “mol” the DNEL of 0.425 mg OH- equals:

(iii) 17 g OH- = 1 mol OH-  0.425 mg OH- = 0.025 mmol OH

 

The value of 0.025 mmol OH-, as the no effect level, is the product of 0.025 mmol/2 = 0.0125 mmol

sodium sulfide (Na2(Sx) x=1,5-5), dissolved in water. This is reconverted to the unit of “milligrams” as follows:

 

(iv) 94.1- 206.35 g sodium sulfide (Na2(Sx) x=1,5-5) = 1mol → 0.0125 mmol sodium sulfide (Na2(Sx) x=1,5-5) = 1.17-2,58 mg sodium sulfide (Na2(Sx) x=1,5-5)

 

Accordingly, a concentration of1.17-1.57 mg/m3was derived as along-term DNEL for local effects of NaOH in workers exposed via inhalation tosodium sulfide (Na2(Sx) x=1,5-5), based on the pH effect.

 

Comparing the different DNEL values for g sodium sulfide (Na2(Sx) x=1,5-5) and sodium hydroxide shows that they are in the same range and thus both mechanisms are addressed adequately by applying this approach for DNEL derivation. The lower value is selected as DNEL for local effects. Therefore,0.84 mg/m3is selectedas the long-term DNEL for local effects in workers exposed via inhalation to Na2Sx (x = 1.5-5).

 

Acute DNEL, local effects by inhalation:sodium sulfide (Na2(Sx) x=1,5-5) is classified as corrosive. Therefore, and in accordance to the ECHA guidance on information requirements and chemical safety assessment – chapter R.8: Characterisation of dose [concentration]-response for human health, May 2008 a DNEL for acute inhalation toxicity should be derived based on the toxicological profile of the substance concerned. This should be derived for a specified fraction of the daily exposure duration (usually 15 minutes for workers).

SCOEL recommendations exist for H2SO4, HCL, H3PO4 and F2, all of which are classified either as R34 or R35 and without doubt have a higher corrosive potential compared to sodium sulfide (Na2(Sx) x=1,5-5) . The above mentioned documents all mention an 8-hour TWA as well as an STEL for 15 minutes. All STEL values are merely derived by applying a factor of 2 to the 8 hour TWA. Based on the toxicological observations as summarised in these SCOEL documents, a factor of 2 for the extrapolation from the long-term DNEL to an acute DNEL should be appropriate. Hence the DNEL for long-term inhalation, local effects for sodium sulfide (Na2(Sx) x=1,5-5) will be used for deriving a DNEL for acute inhalation effect, worker for sodium sulfide (Na2(Sx) x=1,5-5) by multiplying the long-term DNEL with a factor of 2.The long-term DNEL for local effects in workers exposed by inhalation for sodium sulfide (Na2(Sx) x=1,5-5) is 0.84 mg/m3, corresponding to a acute DNEL for local effects in workers for workers of 1.68 mg/m3..

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population