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Description of key information

In the key study, the 90-day inhalation toxicity study with exposure of rats and mice to hydrogen sulfide (Dorman et al., 2004), no toxicologically relevant alterations in haematological indices, serum chemistries, or gross pathology. Therefore, the highest concentration of 80 ppm H2S may be considered as NOAEC for systemic effects.

When comparing the results of the available sub-chronic studies in rats and mice, it becomes obvious that the findings of these inhalation studies are not contradictory. Brennemann et al. (2000), Moulin et al. (2002) and Dorman et al. (2004) found similar targets of toxicity. The main adverse effect caused by 30 and 80 ppm hydrogen sulfide was an exposure-related increased incidence of olfactory neuronal loss (ONL). Thus, the concentration of 10 ppm H2S represents an NOAEC for local effects in the olfactory system.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Data waiving:
exposure considerations
Justification for data waiving:
a short-term toxicity study by the oral route does not need to be conducted because an appropriate inhalation study is available and inhalation is the most appropriate route of administration as based on the provided thorough and rigorous exposure assessment
a sub-chronic toxicity study (90 days) by the oral route does not need to be conducted because an appropriate inhalation study is available and inhalation is the most appropriate route of administration as based on the provided thorough and rigorous exposure assessment
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Study duration:
subchronic

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

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)

[5] Hagg-graph

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

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:

In the key study, the 90-day inhalation toxicity study with exposure of rats and mice to hydrogen sulfide (Dorman et al., 2004), no toxicologically relevant alterations in haematological indices, serum chemistries, or gross pathology. Therefore, the highest concentration of 80 ppm H2S may be considered as NOAEC for systemic effects.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:

In the key study, the 90-day inhalation toxicity study with exposure of rats and mice to hydrogen sulfide (Dorman et al., 2004) the main adverse effect caused by 30 and 80 ppm hydrogen sulfide was an exposure-related increased incidence of olfactory neuronal loss (ONL).

When comparing the results of the available sub-chronic studies in rats and mice, it becomes obvious that the findings of these inhalation studies are not contradictory. Brennemann et al. (2000), Moulin et al. (2002) and Dorman et al. (2004) found similar targets of toxicity.  Thus, the concentration of 10 ppm H2S represents an NOAEC for local effects in the olfactory system.

Repeated dose toxicity: dermal - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

According to regulation (EC) 1272/2008, a classification for specific target organ toxicity – repeated exposure shall be taken into account only when reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

The following observations have been made in experimental animal studies with hydrogen sulfide (read-across to sodium sulfide (Na2Sx (x=1,5 -5):

(i) No systemic toxicity was shown to result from subchronic inhalation exposure in rats or mice to concentrations of hydrogen sulfide up to 80 ppm (NOAECsystemicH2S). Some minor effects on food consumption and body weight were observed, but exposure did not result in toxicologically relevant alterations in haematological indices, serum chemistry, or gross pathology.

(ii) From the key study, a NOAEC of 10 ppm H2S (14 mg/m3 air) for local effects was derived which is based on an increased incidence of olfactory neuronal loss (ONL) at 30 and 80 ppm of hydrogen sulfide.

Since classification as corrosive to respiratory tract is proposed for sodium sulfide, and for the reasons presented above, no classification for specific target organ toxicant (STOT) – repeated exposure, inhalation is required for sodium sulfide Na2Sx (x=1,5 -5).