Sodium O-isobutyl dithiocarbonate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Assessment based on chemistry and data derived from key metabolites

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Assessment of existing data on the substance and key metabolites formed by hydrolysis.

Reason / purpose for cross-reference:

assessment report

Objective of study:

absorption

distribution

excretion

metabolism

other: Hydrolysis

Qualifier:

no guideline followed

Principles of method if other than guideline:

Assessment of gastric hydrolysis and potential adsorption, distribution and excretion of hydrolysis products based on published data for the metabolites

The approach taken is to consider the chemical structure and class of this substance and to look at the existing data set for the substance itself and for the well-defined hydrolysis products.

Searches for similar substances have been performed using commercial directories and the ECHA web-site to help provide a weight of evidence for metabolic processes of the parent substance and the hydrolysis products

GLP compliance:

no

Radiolabelling:

no

Species:

other: Non-animal assessment

Type:

absorption

Results:

The substance is unlikely to be directly absorbed in view of the extremely rapid hydrolysis to carbon disulphide and corresponding aliphatic alcohol

Type:

absorption

Results:

Carbon disulphide and low molecular weight aliphatic alcohols are readily absorbed by inhalation.

Type:

distribution

Results:

Impart to spleen and liver, mainly through blood chemistry changes, demonstrate distribution of the hydrolysis products and their metabolites

Type:

metabolism

Results:

Low molecular weight aliphatic alcohols metabolise to carbon dioxide and water and used in metabolic processes associated with energy.

Type:

excretion

Results:

No evidence of significant excretion of parent substance or hydrolysis products through urine

Type:

clearance

Results:

Low molecular weight aliphatic alcohols can be excreted through air
Carbon disulphide shown to be excreted through air exchange

Details on absorption:

• The substance is unlikely to be absorbed orally in view of the extremely rapid hydrolysis to carbon disulphide and corresponding aliphatic alcohol
• The substance is considered highly irritating to skin and there is no evidence of dermal absorption, although in the presence of moisture, hydrolysis is likely. It is possible that the reported local dermal reaction is directly linked to reactivity on the skin surface.
• Inhalation exposure to the parent substance is not considered significant, although exposure to the hydrolysis products cannot be ignored.

Details on distribution in tissues:

• The metabolites are considered to be readily transported and metabolised further.
• Impact on organs including spleen and liver are consistent with carbon disulphide and alcohols.

Test no.:

#1

Transfer type:

blood/placenta barrier

Remarks:

Research into carbon disulphide demonstrates transfer across the placenta following inhalation exposure.

Observation:

slight transfer

Remarks:

Not quantified

Details on excretion:

No evidence of excretion of the parent substance or immediate hydrolysis products. Kidneys and urine appear not to be affected in any studies performed on the parent or hydrolysis products.

Metabolites identified:

yes

Remarks:

Radiolabelled material was found to be excreted in urine in the form of complex sulphur-containing thiocarbonates

Details on metabolites:

Low molecular weight aliphatic alcohols metabolise to carbon dioxide and water and used in metabolic processes associated with energy.

Enzymatic activity measured:

Not specified

Conclusions:

Non accumulative

Executive summary:

From evidence derived from direct testing and from information obtained on the hydrolysis products, it can be concluded that:

 

• The substance is unlikely to be absorbed orally in view of the extremely rapid hydrolysis to carbon disulphide and corresponding aliphatic alcohol


• The substance is considered highly irritating to skin and there is no evidence of dermal absorption, although in the presence of moisture, hydrolysis is likely. It is possible that the reported local dermal reaction is directly linked to reactivity on the skin surface.


• A human study shows that CS₂ is absorbed through the skin from aqueous solutions.


• Inhalation exposure to the parent substance is not considered significant, although exposure to the hydrolysis products cannot be ignored.


• The metabolites are considered to be readily transported and metabolised further.


• Impact on organs including spleen and liver are consistent with carbon disulphide and alcohols.


• No evidence of excretion of the parent substance or immediate hydrolysis products. Kidneys and urine appear not to be affected in any studies performed on the parent or hydrolysis products.


• CS₂ is eliminated via exhaled air. After termination of exposure, the elimination of unaltered CS₂ via the exhaled air amounts roughly to 5 -50% of the absorbed amount.


• Unaltered CS₂ is hardly excreted via the kidneys: less than 1%


• Radiolabelled material was found to be excreted in urine in the form of complex sulphur-containing thiocarbonates suggesting incorporation of carbon disulphide into other substances


• Low molecular weight aliphatic alcohols can be excreted through air, but typically metabolise to carbon dioxide and water and used in metabolic processes associated with energy.


• The substance and the hydrolysis products and biological metabolites are not considered accumulative

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Xanthates are metabolized in the human or animal bodies to carbon disulfide(CAS# 75-15-0)due to presence of the CS₂/cysteine (glutathione) conjugation product , 2-thiothiazolidine-4-carboxilic acid (TTCA) in urine of exposed workers or animals.

The lungs are the primary rout of excretion of unmetabolized carbon disulfide in humans and animals exposed by inhalation, whereas the kidneys are the primary route of excretion of carbon disulfide metabolites.

Assessment of the toxicokinetics behavior of the substance to the extent that can be derived from the relevant available information..(Donoghue A.M., Occup. Med. Vol. 48, 469-470,1998)

The expired CS₂in the exhaled air was monitored in the study of the metabolism of xanthates with humans and guinea pigs. After injection of 50 or 100mg/kg of sodium ethyl xanthate in guinea pigs up to 7% was expired as CS₂during 8 hours. The rate of elimination was dose-related, however the total percentage recovered was independent of dose after administration of sodium or

potassium xanthate. Co injection of ethyl alcohol with sodium ethyl xanthate increased rate of CS₂elimination and greater total recovery.

Study of CS₂elimination in breath after oral intake in human volunteers of 150 and 250 mg of sodium ethyl xanthate showed a maximum rate 13-57 µm/m³/h between 1-2h, complete elimination by 6h.

Sodium ethyl xanthate is metabolized to CS₂(CAS# 75-15-0) due to presence in urine of exposed workers, of the CS₂/cysteine conjugated product, 2-thiothiazolidine-4-carboxylic acid (TTCA).

The metabolite was detected in urine of a worker exposed to extensive skin contamination with the xanthate powder

and solution during the reagent mixing. An illness consisting of predominantly gastrointestinal symptoms began 20h after the exposure.

Carbon disulphide is readily absorbed by inhalation.6 Studies also indicate that carbon disulphide as a liquid, such as a solvent or aqueous solution, is absorbed through the skin. Studies in humans have shown that approximately 70–90% of carbon disulphide absorbed into the body is metabolised, with 1% excreted unchanged and the remainder exhaled. Due to its affinity for lipid-rich tissues and organs, carbon disulphide rapidly disappears from the bloodstream. In humans, carbon disulphide is metabolised to give organo-sulphur compounds such as thiourea in the urine. Studies in rats and guinea pigs have indicated that carbon disulphide is initially accumulated in the liver, brain, blood and adrenals.

Carbon disulfide is metabolized by cytochrome P-450 to an unstable oxygen intermediate which may either degrade to atomic sulfur and carbonyl sulfide or hydrolyze to form atomic sulfur and monothiocarbonate. The atomic sulfur may either bind to macromolecules or be oxidized to sulfate. The carbonyl sulfide may be converted to monothiocarbonate by carbonic anhydrase. Dithiocarbamates are the products of the reaction of CS2with amino acids. In vitro studies found that carbon disulfide reacts with amino acids in human blood, the half time of this reaction was 6,5h. Thiocarbamide has been found in the urine of exposed workers. After inhalation exposure of male human , up to 90% of the retained carbon disulfide was metabolized , the remainder was excreted by the lungs (6-10%) and in urine (about 1%) Carbon disulfide is oxidized by the liver mixed-function oxidase system to carbonyl sulfide and then undergoes further desulfurizatioin releasing elemental sulfur.

Metabolism of xanthates:

Sodium ethyl xanthate is metabolized to CS₂(CAS# 75-15-0)due to presence in urine of exposed workers, of the CS₂/cysteine conjugated product, 2-thiothiazolidine-4-carboxylic acid (TTCA). The metabolite was detected in urine of a worker exposed to extensive skin contamination with the xanthate powder and solution during the reagent mixing. An illness consisting of predominantly gastrointestinal symptoms began 20h after the exposure.(Donoghue A.M., Occup. Med. Vol. 48, 469-470,1998)

Study of CS₂elimination in breath after oral intake in human volunteers of 150 and 250 mg of sodium ethyl xanthate showed a maximum rate 13-57 µm/m³/h between 1-2h, complete elimination by 6h(Merlevede E., Peters J., 1965, Archives of the Belgian Medical Society, 23(8): 513-551).

Metabolism of carbon disulfide(CAS# 75-15-0)

Carbon disulfide is metabolized by cytochrome P-450 to an unstable oxygen intermediate which may either degrade to atomic sulfur and carbonyl sulfide or hydrolyze to form atomic sulfur and monothiocarbonate. The atomic sulfur may either bind to macromolecules or be oxidized to sulfate. The carbonyl sulfide may be converted to monothiocarbonate by carbonic anhydrase(Beauchamp R.D., et all, 1983, CRC Critical Reviews in Toxicology 11: 169-278)

Dithiocarbamates are the products of the reaction of CS₂with amino acids. In vitro studies found that carbon disulfide reacts with amino acids in human blood, the half time of this reaction was 6,5h. Thiocarbamide has been found in the urine of exposed workers(Pergal M.,et all , 1972, Arch. Environ Health 25:42-44). After inhalation exposure of male human , up to 90% of the retained carbon disulfide was metabolized , the remainder was excreted by the lungs (6-10%) and in urine (about 1%)(McKee R.W., et all, JAMA 122:217-222).

Carbon disulfide is oxidized by the liver mixed-function oxidase system to carbonyl sulfide and then undergoes further desulfurizatioin releasing elemental sulfur(Dalvi R.R. , et all, 1974, Life Sci. 14:1785-1796).

Conjugation of carbon disulfide or carbonyl sulfide with endogenous glutathione yields thiazolidine-2-thione-4-carboxylic acid (TTCA) and 2-oxythiazolidine-4-carboxylic acid, respectively(Van Doorn R., et all,1981, Arch. Environ. Health 36:289-2970). High concentration about 320mM of TTCA were detected in the urine of women exposed to approximately 32 ppm (100 mg/m³) CS₂through inhalation.