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Neurotoxicity

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Description of key information

Na2S inhibited cytochrome oxidase and carbonic anhydrase prepared from brains of male rats in a concentration-dependent manner. Extensive disruption of respiratory and related mitochondrial functions was determined in homogenates of synaptosomes prepared from brains of CDI mice treated i.p. with Na2S.
Treatment of male Wistar rats with 11.7 mg/kg Na2S i.p. caused a partial inhibition of GABA and dopamine uptake, and it strongly inhibited veratridine-dependent release of these neurotransmitters and reduced veratridine-dependent changes in the trans-membrane potential in synaptosomes isolated from the hemispheres. However, single doses of Na2S (80-200 mg/kg) administered i.p. to rats indicated that very high doses are incapable of producing cerebral necrosis by a direct histotoxic effect.
Inhalation of hydrogen sulfide resulted in a marked, but reversible, decrease in the incorporation of leucine in the cerebral protein and myelin accompanied by a decreased activity of lysosomal acid proteinase after inhalation exposure of adult female mice at 100 ppm H2S for 2 h.
After repeated inhalation exposure of male rats (5 d, 3h/d) to low levels of H2S, the total power of hippocampal EEG theta activity increased in a concentration-dependent manner in both dentate gyrus and CA1 region that required two weeks for a complete recovery. Neocortical EEG and LIA (Large Amplitude Irregular Activity) were unaffected following exposure to 100 ppm H2S.
Determination of serotonin and norepinephrine levels in developing rat cerebellum and frontal cortex of pups from rats exposed for 7 h/d (GD 5 until PND 21) suggested that alterations of monoamine levels induced by H2S may produce long-lasting neurochemical changes in the CNS.
Short-term exposure of adult male rat to H2S for 3 h/d for 5 d significantly reduced motor activity, water maze performance, and body temperature following exposure to H2S concentrations ≥ 80 ppm, but did not affect regional brain catecholamine concentrations.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

READ ACROSS CONCEPT

Valid toxicological data on neurotoxicity specifically for strontium sulfide from animal studies are not available. Therefore, because of the lack of appropriate experimental data, read-across from studies with sulfides and strontium compounds is proposed based on the following reasoning:

Read-across to sulfide:

The readily water-soluble compound strontium sulfide will initially dissociate upon dissolution in water and/or relevant physiological media into strontium and sulfide ions.

However, sulfide anions will react with water in a pH-dependant reverse dissociation to form hydrogensulfide anions (HS-) or H2S, respectively, according to the following equation:

H2S  H+ + HS-  2H+ + S2-

The dissociation behaviour is presented in the Hägg graph reported under IUCLID section 5.1.2 Hydrolysis.

The pKa values for the first and second dissociation steps of H2S are 7.0 and 12.9 (for details, refer to the IUCLID section on dissociation constant), respectively. Therefore, at neutral 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. Conversely, at gastric pH (pH 1-2), non-dissociated H2S will be the predominant species.

In conclusion, under physiological conditions, inorganic sulfides or hydrogensulfides as well as H2S will dissociate to the respective species relevant to the pH of the physiological medium, irrespective of the nature of the “sulfide”, which is why read-across between these substances and H2S is considered to be appropriate without any restrictions for the purpose of hazard and risk assessment of strontium sulfide.

Read-across to Strontium:Upon dissolution in water and/or physiological media, dissociation of strontium sulfide to release Sr2+ions may initially be expected.

However, based on the established fact that strontium ions may form poorly soluble species for example with physiologically present carbonate ions, the bioaccessibility/bioavailability may vary between different physiological conditions. Notwithstanding this limitation, it is considered justified to read-across from available data on strontium dichloride. In this context, the water solubility of a substance is used as a first approximation of bioavailability:

-     strontium dichloride is highly water soluble with ca. 538 g/L at 20°C/pH ca. 7 (solubility at pH 1.5; 257.5 g/L at 37°C)

In comparison, the water solubility of strontium sulfide is 120.6 ± 1.9 g/L at 24 ± 1.0°C pH 12.9.

In conclusion, read across from strontium chloride to strontium sulfide is considered as justified since the toxicity of these substances may reasonably be considered to be determined by the availability of Sr cations. It is noted that although SrS is a strong base (pH 12.6 for a 1% solution - source: Anonymous, 2009), substantial neutralisation in the gastrointestinal tract at pH-levels of approx. 1.5 – 2 may nevertheless be anticipated.

Strontium:Evidence for neurological activity of strontium was obtained from a number of in vitro investigations. In a calcium-free medium, strontium ions weakly supported the generation of excitatory postsysnaptic potentials following stimulation of guinea pig cervical ganglia (i. e., the release of acetylcholine was less efficient than when calcium was present) (s_McLachlan_1977). Incubation of vasa deferentia isolated from guinea pigs showed that both strontium and barium cations can substitute for calcium ions in the release of noradrenaline at adrenergic nerve terminals.

It was concluded that all these cations act through the same site at some stage in the process of potassium induced transmitter release (s_Nakazato_1980). Perfusion through acutely denerved cats´ adrenal glandsby strontium in calcium-free Locke´s solution resulted in an intense catecholamine secretion and restored the response to acetylcholine and excess potassium (s_Douglas_1964). Findings that the stimulating effect of strontium also persisted in glands perfused with EDTA led to the conclusion that strontium can substitute for calcium in the secretory process without liberation of endogeneous calcium from some intracellular binding sites. The sequestration of different divalent cations including strontium was examined, in comparison to calcium, by mitochondria and smooth endoplasmic reticulum from isolated presynaptic nerve terminals (s_Rasgado-Flores_1987). Strontium cations were less effective (by about 50 to 60%) than calcium ions.

Sulfides:From mechanistic studies with intraperitoneal injection of sodium hydrogensulfide to rats it can be concluded that the lung and not the brain is the primary site of action of hydrogen sulfide, with an afferent neural signal from the lung via the vagus inducing apnea. In addition, substantial changes in neurotransmitter amino acids in the brainstem responsible for neuronal control of breathing were noted. Analyses of effects of sodium hydrogensulfide on brain transmitter systems and monoamine oxidase (MAO) activity after i. p. administration to rats led to the suggestion that inhibition of MAO may be an important contributing factor to the mechanisms underlying loss of respiratory drive after H2S exposure.

Mechanistic in-vitro and in-vivo studies with Na2S revealed that sulfide toxicity can be ascribed to the inhibition of cytochrome oxidase as key enzyme of the respiratory chain. Sodium sulfide has also been shown to strongly inhibit neuronal cytochrome oxidase and carbonic anhydrase causing disruption to respiratory and mitochondrial functions in the rat brain in vitro. Inhibitory effects on synaptosomal respiration and transmitter kinetics were shown after i. p. injection into rats with sodium sulfide.

In in-vivo studies with short-term exposures of rats to H2S, a cumulative effect on hippocampal EEG theta activity was observed at high exposure levels that required two weeks for a complete recovery. Neocortical EEG and Large Amplitude Irregular Activity (LIA) were unaffected. Furthermore, behavioural toxicity was observed in rats only at higher concentrations (≥80 ppm) of H2S. But, regional brain catecholamine levels or performance on the fixed-interval (FI) schedule were not affected. Perinatal exposure of pregnant rats to hydrogen sulfide resulted in alterations of serotonin and norepinephrine levels in the cerebellum and frontal cortex of the pups.

Reference:Anonymous (2009): Solfuro di strontio, ECOL Studio S. R. L., Via Dei Bichi 293, 55100 Lucca, Italia, 2009-12-30

Justification for classification or non-classification

Based on mechanistic in-vitro and in-vivo (i.p.) studies with NaHS and Na2S, it is not possible to derive a no effect level or low effect level which is relevant for real exposure situations. This holds also true for the study with examination of effects on hippocampal EEG theta activity following short-term inhalation exposure of rats to H2S, because it cannot be ruled out that these changes are related to a sensory olfactory stimulation, and it is not known whether these changes are related to any adverse clinical effects. However, in short-term behavioural study in rats, some effects on motor activity were observed at high exposure levels. However, study duration was only 5 days, and it is likely that adaptation occurs after longer-term exposure durations, because no behavioural effects were observed in a 90-day inhalation toxicity study with H2S at the same exposure level. Although it was shown that perinatal exposure of pregnant rats to hydrogen sulfide resulted in alterations of serotonin and norepinephrine levels in the cerebellum and frontal cortex of pups, detailed behavioural tests in offspring of dams exposed by inhalation to H2S until gestation day 19 and dams and pups from postnatal day 5 to 18 revealed no clinical effects.

Therefore, it can be concluded that neurotoxicological effects of Na2S and NaHS could be demonstrated in-vitro and following i.p. injection, but subchronic inhalation exposure to H2S did not result in clinical effects of neurotoxicity in adult rats and their offspring.