Sodium O-isobutyl dithiocarbonate

Basic toxicokinetics

Administrative data

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.

Cross-reference

Reason / purpose for cross-reference:

assessment report

Reference

Endpoint:

hydrolysis

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

Special study performed to confirm rapid hydrolysis of potassium and sodium xanthates in simulated gastric fluid with identification of key metabolites.
This study is used to justify the use of surrogate data in animal testing on the basis that if ingested, the substance will rapidly degrade.

Qualifier:

no guideline followed

Principles of method if other than guideline:

study of the decomposition of four samples of xanthates in simulated gastric fluid; sodium soamyl xanthate, sodium isobutyl xanthate, sodium ethyl xanthate and potassium isoamyl xanthate.
The chemical reaction for this decomposition is:

Xanthate Salt + Hydrochloric acid Alcohol + Sodium Chloride + Carbon Disulphide

The reaction between simulated gastric fluid and the xanthate salts was carried out at 0oC for reasons of safety, as the reaction was expected to occur very quickly. The reaction mixture was then allowed to warm to room temperature over 1 hour, the final temperature being 25oC. A high degree of degradation at this temperature would lead to the inference that degradation would be at least as complete, if not more so, in actual gastric conditions.

Following the reaction solvent was added to produce a biphasic mixture, and the resulting organic
phases were analysed by GC-MS to confirm the presence of the corresponding alcohols. These
alcohols were quantified by comparison to known standards in order to confirm the completeness of the reaction, and to show that these salts behave in the same way under these reaction conditions.

Radiolabelling:

no

Analytical monitoring:

yes

Buffers:

Performed at pH 1.5 in synthetic gastric fluid

Details on test conditions:

Performed at 5 g/l to simulate possible concentration following ingestion
Performed at low temperatures for safety reasons due to exothermic nature of reaction

Duration:

1 h

pH:

1.5

Temp.:

0 °C

Initial conc. measured:

ca. 5 000 mg/L

Remarks:

Performed at initial temperature of 0 C, but in view of exothermic reaction, temperature will have risen by the end of the reaction.

Number of replicates:

One replicate per substance
A number of xanthates were evaluated as part of this study; all showed the same outcome

Positive controls:

no

Negative controls:

no

Statistical methods:

Not required

Preliminary study:

No

Transformation products:

yes

No.:

#1

No.:

#2

No.:

#3

No.:

#4

Details on hydrolysis and appearance of transformation product(s):

Exothermic reaction. No direct measurement of carbon disulphide possible, but elemental sulphur noted (estimated to be as dissolved sulphur dioxide or sulphates

% Recovery:

0

pH:

1.5

Temp.:

0 °C

Duration:

1 h

Remarks on result:

other: No parent material detected

Remarks on result:

not determinable because of methodological limitations

Remarks:

Too rapid to determine a rate constant

Details on results:

Rapid exothermic reaction in simulated gastric fluid at a loading of 5g/l

Sodium isoamyl xanthate, sodium isobutyl xanthate and sodium ethyl xanthate were added to separate solutions of simulated gastric fluid at 0 C over 1 hour. The low starting temperature was to prevent reaction occurring too quickly, for reasons of safety.

Following the reaction, a liquid-liquid extraction was performed with ethyl acetate and the organic solvent analysed using GCMS. The extracts were compared to a standard curve of ethanol, isoamyl alcohol and isobutyl alcohol were quantified.

Based on analysis of the alcohols. degradation of sodium isobutyl xanthate was found to be > 96% under the experimental conditions and degradation of sodium isoamyl xanthate was found to be > 75% under the experimental conditions.  However, no xanthates could be found at the end of the exposure period

The degradation of sodium ethyl xanthate could not be quantified under the experimental conditions and assumed 100%

To confirm that potassium salts will behave in a similar manner, potassium isoamyl xanthate was added to simulated gastric fluid under the same conditions as the sodium salts above. A liquid-liquid extraction was performed with ethyl acetate and the organic solvent analysed using GCMS. Isoamyl alcohol was observed in the resulting gas chromatogram, as expected.

NMR spectroscopy did not provide any further evidence of the presence of xanthate post addition to gastric fluid. 

To confirm that the sodium or potassium remains in solution as the chloride salt, ICP-OES analysis was carried out on the aqueous phase of the reaction mixture, as well as on the simulated gastric fluid with the difference between the two measurements being an indication of how much sodium or potassium has been added as a result of the xanthate degradation. The analysis showed increased levels of potassium and sodium in the gastric fluid phase upon addition of potassium and sodium xanthates respectively. This provides further evidence that the potassium salts behave in a similar manner to the sodium salts under the experimental conditions.

The increase in sodium could not be quantified owing to the high levels of Na observed, and the addition of Na from processing.

For Potassium Isoamyl Xanthate, a significant increase in potassium was observed and the potassium and sodium salts can be considered as behaving in identical manner.

Carbon disulphide was not detected and due to limitations of the methods detection of carbon dioxide or sulphur dioxide was not possible.  There was no reported odour of carbon dislulphide.

Executive summary:

Based on analysis of the alcohols. degradation of sodium isobutyl xanthate was found to be > 96% under the experimental conditions a

To confirm that potassium salts will behave in a similar manner, potassium isoamyl xanthate was added to simulated gastric fluid under the same conditions as the sodium salts above. A liquid-liquid extraction was performed with ethyl acetate and the organic solvent analysed using GCMS. Isoamyl alcohol was observed in the resulting gas chromatogram, as expected.

NMR spectroscopy did not provide any further evidence of the presence of xanthate post addition to gastric fluid. 

To confirm that the sodium or potassium remains in solution as the chloride salt, ICP-OES analysis was carried out on the aqueous phase of the reaction mixture, as well as on the simulated gastric fluid with the difference between the two measurements being an indication of how much sodium or potassium has been added as a result of the xanthate degradation. The analysis showed increased levels of potassium and sodium in the gastric fluid phase upon addition of potassium and sodium xanthates respectively. This provides further evidence that the potassium salts behave in a similar manner to the sodium salts under the experimental conditions.

The increase in sodium could not be quantified owing to the high levels of Na observed, and the addition of Na from processing.

For Potassium Isoamyl Xanthate, a significant increase in potassium was observed and the potassium and sodium salts can be considered as behaving in identical manner.

Carbon disulphide was not detected and due to limitations of the methods detection of carbon dioxide or sulphur dioxide was not possible.  There was no reported odour of carbon dislulphide.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2022

Report date:

2022

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

other: Hydrolysis

Test guideline

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

Test material

Test material information

Constituent 1

Reference substance name:

Sodium O-isobutyl dithiocarbonate

EC Number:

246-805-2

EC Name:

Sodium O-isobutyl dithiocarbonate

Cas Number:

25306-75-6

Molecular formula:

C5H10OS2.Na

IUPAC Name:

sodium [(2-methylpropoxy)methanethioyl]sulfanide

Constituent 2

Reference substance name:

Sodium isobutyl xanthate

IUPAC Name:

Sodium isobutyl xanthate

Test material form:

solid: particulate/powder

Radiolabelling:

no

Test animals

Species:

other: Non-animal assessment

Results and discussion

Main ADME results

Main ADME results 1

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

Main ADME results 2

Type:

absorption

Results:

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

Main ADME results 3

Type:

distribution

Results:

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

Main ADME results 4

Type:

metabolism

Results:

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

Main ADME results 5

Type:

excretion

Results:

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

Main ADME results 6

Type:

clearance

Results:

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

Toxicokinetic / pharmacokinetic studies

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.

Transfer into organs

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.

Metabolite characterisation studies

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

Enzymatic activity measured:

Not specified

Applicant's summary and conclusion

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