Proxan-sodium

Eye irritation

Administrative data

Endpoint:

eye irritation: in vivo

Remarks:

Note that in-vivo eye irritation should not have been attempted in view of results of in-vivo skin irritation. These historical data are included for information only

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

Study provided on similar substance to help build up a weight of evidence demonstrating potential for read-across between the xanthates
Note that in-vivo eye irritation should not have been attempted in view of results of in-vivo skin irritation. These historical data are included for information only

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across: supporting information

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 eight samples of xanthates in simulated gastric fluid; sodium isoamyl xanthate, sodium isobutyl xanthate, sodium ethyl xanthateр potassium isoamyl xanthate, potassium ethyl xanthate (PEX). sodium isopropyl xanthate (SIPX), Potassium amyl xanthate and potassium isobutyl 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, sodium ethyl xanthateр  potassium isoamyl xanthate, potassium ethyl xanthate (PEX), sodium isopropyl xanthate (SIPX), Potassium amyl xanthate and potassium isobutyl 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 isopropyl xanthate (SIPX), was found to be  100% under the experimental conditions and degradation of potassium amyl xanthate was found to give 93% under the experimental conditions , potassium isobutyl xanthate was found to give 94%, sodium isobutyl xanthate was found to give 96% under the experimental conditions .  However, no xanthates could be found at the end of the exposure period.

To confirm that potassium salts will behave in a similar manner, potassium xanthates 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 Xanthates, 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 isopropyl xanthate (SIPX), was found to be  100% under the experimental conditions and degradation of potassium amyl xanthate was found to give 93% under the experimental conditions , potassium isobutyl xanthate was found to give 94%, sodium isobutyl xanthate was found to give 96% under the experimental conditions .  However, no xanthates could be found at the end of the exposure period.

 

To confirm that potassium salts will behave in a similar manner, potassium xanthates 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. The corresponding 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 Xanthates, 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.

 

Cross-reference 2

Reason / purpose for cross-reference:

read-across: supporting information

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

not specified

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 O-isobutyl dithiocarbonate

Constituent 2

Reference substance name:

Sodium isobutyl xanthate

IUPAC Name:

Sodium isobutyl xanthate

Test material form:

other: water solution

Test animals / tissue source

Species:

rabbit

Test system

Vehicle:

water

Amount / concentration applied:

0.1 ml/eye as water solution pH=10.1, containing 456,1g/dm3 of the substance

Duration of treatment / exposure:

introduced into the conjunctival sacs of the right eye

Observation period (in vivo):

Observation were made after 1h, 24, 48 hours and then after 7 days

Number of animals or in vitro replicates:

1 male

Details on study design:

introduced into the conjunctival sacs of the right eye

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

conjunctivae score

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not reversible

Remarks on result:

probability of severe irritation

Results 2

Irritation parameter:

iris score

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not reversible

Remarks on result:

probability of severe irritation

Results 3

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not reversible

Remarks on result:

probability of severe irritation

Results 4

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not reversible

Remarks on result:

probability of severe irritation

Results 5

Irritation parameter:

other: IIPO

Time point:

other: 7

Score:

110

Reversibility:

not fully reversible within:

Remarks on result:

probability of severe irritation

Results 6

Irritation parameter:

other: IIPO

Time point:

other: 1-48 h

Score:

77.7

Reversibility:

not fully reversible within:

Remarks on result:

probability of severe irritation

Irritant / corrosive response data:

After 1h, ¾ of the cornea surface was clouded,in the iris was noted congestion. The conjunctiva was reddened, red beet color, oedema, and discharge on palpebra. After 24h and 48h the changes in eye became more intense, pupil was visible in lower part of the eye, details of iris was not visible, the pupil reacted slowly on light. After 7 days changes in the eye became more intense, ¾ of cornea was clouded, in lower part of the cornea details of iris was not visible. In the cojunctiva of the lower palpebra necrosis was noted.
NOTE : This study should have been terminated immediately

Applicant's summary and conclusion

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

Sodium isobutyl xanthate should be consider as seriously injured substance of the rabbit eyes.

Executive summary:

Study provided on similar substance to help build up a weight of evidence demonstrating potential for read-across between the xanthates

Note that in-vivo eye irritation should not have been attempted in view of results of in-vivo skin irritation.  These historical data are included for information only