Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Various peer-reviewed articles discussing toxicokinetic aspects of of sulphur (and compounds), public literature, some restrictions, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Autoradiographic observations on the uptake of S35 in the genital organs of the female rat and rabbit after injection of labeled sodium sulfate.
Author:
Bostrom H, Odeblad E
Year:
1952
Bibliographic source:
Acta Endocrinol. (Copenh);10(1):89-96
Reference Type:
publication
Title:
On the enzymatic exchange of the sulfate group of chondroitinsulfuric acid in slices of cartilage.
Author:
Bostrom H, Mansson B
Year:
1952
Bibliographic source:
J.Biol.Chem.;196(2):483-8
Reference Type:
publication
Title:
On the metabolism of the sulfate group of chondroitinsulfuric acid.
Author:
Bostrom H
Year:
1952
Bibliographic source:
J.Biol.Chem.;196(2):477-81
Reference Type:
publication
Title:
Rate of excretion of radioactive sulphur and its concentration in some tissues of the rat after intraperitoneal administration of labeled sodium sulphate.
Author:
Dziewiatkowski D
Year:
1949
Bibliographic source:
J.Biol.Chem.;178:197-202
Reference Type:
publication
Title:
Metabolic acidosis after sulfur ingestion.
Author:
Blum JE, Coe FL
Year:
1977
Bibliographic source:
N.Engl.J.Med.;297(16):869-70
Reference Type:
publication
Title:
The oxidation of sulfide to thiosulfate by metalloprotein complexes and by ferritin.
Author:
Baxter CF, van Reen R
Year:
1958
Bibliographic source:
Biochim.Biophys.Acta;28(3):573-8
Reference Type:
publication
Title:
Some aspects of sulfide oxidation by rat-liver preparations.
Author:
Baxter CF, van Reen R
Year:
1958
Bibliographic source:
Biochim.Biophys.Acta;28(3):567-73.
Reference Type:
publication
Title:
Hepatic sulfite oxidase. The nature and function of the heme prosthetic groups.
Author:
Cohen HJ, Fridovich I
Year:
1971
Bibliographic source:
J.Biol.Chem.;246(2):367-73
Reference Type:
publication
Title:
Accidental sulfur poisoning in a group of Holstein heifers.
Author:
Gunn M, Baird J, Nimmo Wilkie J
Year:
1987
Bibliographic source:
Can.Vet.J.;28(4):188-92
Reference Type:
publication
Title:
A critical review of the literature on hydrogen sulphide toxicity.
Author:
Beauchamp R, Bus J, Popp J, Boreiko C, Andjelkovich D
Bibliographic source:
CRC Crit.Rev.Tox.;13(1):25-97

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
In accordance with column 2 of REACH Annex VIII-X, an assessment of the toxicokinetic behaviour of the substance should be derived using all available studies. No quantitative data are available on the toxicokinetics of elemental sulfur via the oral, dermal and respiratory routes, neither in animals nor in humans and no specific key studies are identified. A number of peer-reviewed articles shed some qualitative light on elemental sulfur toxicokinetics.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
elemental sulphur (various forms, not always clearly specified)

Test animals

Species:
other: rats, rabbits, dogs, cattle, humans
Strain:
other: various
Sex:
male/female

Administration / exposure

Route of administration:
other: oral, dermal and i.p.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
No quantitative data are available on absorption of elemental sulfur via the oral and inhalation route, neither in animals nor in humans.
Details on distribution in tissues:
Once absorbed as sulphide, 35S is distributed in rats as sulfates formed in the body, mostly in tissue containing mucopolysaccharides such as cartilage, trachea, intestinal mucosa, skin and genitals (Bostrom and Odeblad, 1952; Bostrom and Mansson, 1952; Bostrom, 1952).
Details on excretion:
Excretion of H2S by the lungs after parenteral administration of a solution of sulfide salts (sodium35S-sulfide) to dogs, rabbits or to rats is minimal and can be considered as negligible (Beauchamp et al, 1984). Urinary excretion of35S after intraperitoneal administration of sodium sulfate to rats was approximately 67% of the radioactivity within 24h, 85% after 120 h with a recovery of 10 % in the faeces within 120 h (Dziewiatkowski, 1949).

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
In non-ruminant animals, including man, ingested elemental sulfur is probably converted first to hydrogen sulfide, by colonic bacteria, absorbed and then converted to sulfate (Blum and Coe, 1977) which enters then the normal sulfate body-pool, and, in the liver and the kidney into thiosulfate by an enzymatic activity associated with the mitochondria (Baxter and van Reen, 1958). The enzyme system which is most probably involved is the cytochrome oxidase system which uses molecular oxygen. Cohen and Fridovich (1971) demonstrated by spectral similarity that the sulfite oxidase activity associated with the microsomal fraction of bovine liver is due to a cytochrome b type oxidase. Ferritin seems to convert H2S into thiosulfate in the intestinal mucosa (Baxter and van Reen, 1958).
The absorbed sulfur compounds are incorporated into endogenous sulfur-containing molecules.

In ruminants, sulfur is rapidly reduced in the rumen to sulfite and hydrogen sulphide, some of the hydrogen sulfide is oxidised to sulfate (Gunn, Baird and Nimmo Wilkie, 1987). While some of the hydrogen sulfide is incorporated into microbial protein before being absorbed in the form of essential amino-acids methionine and cysteine, excessive sulfur production within the rumen results in a build-up of toxic hydrogen sulfide gas (H2S). Since the liver efficiently removes sulfide absorbed into the portal vasculature, toxicity of H2S in ruminants is apparently due to eructation (i.e., ejection of gas or air through the mouth from the stomach) and inhalation of H2S produced in the rumen. It is not possible with the available literature to quantify this process. Once H2S has been absorbed, it is metabolised by three different pathways:
1. Oxidation to sulfate and thiosulfate;
2. Methylation to methanethiol and dimethyl sulfide;
3. Reaction with metallo- and disulfide-containing proteins.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): low bioaccumulation potential based on study results
In non ruminant animals (and humans), once absorbed, sulfur gets distributed mostly in tissue containing mucopolysaccharides such as cartilage, trachea, intestinal mucosa, skin and genitals. Majority of sulfur gets excreted via urine and faeces.

In ruminants, sulfur is rapidly reduced in the rumen to sulfite and hydrogen sulphide, with some of the hydrogen sulfide being oxidised to sulfate. Once absorbed, H2S is metabolised by three different pathways:
 
1. Oxidation to sulfate and thiosulfate;
2. Methylation to methanethiol and dimethyl sulfide;
3. Reaction with metallo- and disulfide-containing proteins.
Executive summary:

No quantitative data are available on absorption of elemental sulfur via the oral and inhalation route, neither in animals nor in humans.

Once absorbed as sulphide, radiolabelled sulphur (35S) is distributed in rats as sulfates formed in the body, mostly in tissue containing mucopolysaccharides such as cartilage, trachea, intestinal mucosa, skin and genitals.

 

Excretion of H2S by the lungs after parenteral administration of a solution of sulfide salts (sodium 35S-sulfide) to dogs, rabbits or to rats is minimal and can be considered as negligible. Urinary excretion of 35S after intraperitoneal administration of sodium sulfate to rats was approximately 67% of the radioactivity within 24h, 85% after 120 h with a recovery of 10 % in the faeces within 120 h.

 

In non-ruminant animals, including man, ingested elemental sulfur is probably converted first to hydrogen sulfide, by colonic bacteria, absorbed and then converted to sulfate which enters then the normal sulfate body-pool, and, in the liver and the kidney into thiosulfate by an enzymatic activity associated with the mitochondria. The enzyme system which is most probably involved is the cytochrome oxidase system which uses molecular oxygen. It has been demonstrated by spectral similarity that the sulfite oxidase activity associated with the microsomal fraction of bovine liver is due to a cytochrome b type oxidase. Ferritin seems to convert H2S into thiosulfate in the intestinal mucosa.

 

The absorbed sulfur compounds are incorporated into endogenous sulfur-containing molecules.

 

In ruminants, sulfur is rapidly reduced in the rumen to sulfite and hydrogen sulphide, some of the hydrogen sulfide is oxidised to sulfate. While some of the hydrogen sulfide is incorporated into microbial protein before being absorbed in the form of essential amino-acids methionine and cysteine, excessive sulfur production within the rumen results in a build-up of toxic hydrogen sulfide gas (H2S). Since the liver efficiently removes sulfide absorbed into the portal vasculature, toxicity of H2S in ruminants is apparently due to eructation (i.e., ejection of gas or air through the mouth from the stomach) and inhalation of H2S produced in the rumen. It is not possible with the available literature to quantify this process. Once H2S has been absorbed, it is metabolised by three different pathways:

 

1. Oxidation to sulfate and thiosulfate;

2. Methylation to methanethiol and dimethyl sulfide;

3. Reaction with metallo- and disulfide-containing proteins.