Proxan-sodium

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

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:

Read-across from potassium salt
The potassium salty xanthates is considered suitable as a source of data for the corresponding sodium salt xanthates
Considered valid for read-across for purposes of classification.
No further vertebrate testing can be justified.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across: supporting information

Cross-reference 2

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.

 

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Thirty-day inhalation toxicity study with potassium amyl xanthate

Author:

Canadian Centre for Occupational Health and Safety,

Year:

1994

Bibliographic source:

Cheminfo 202, 1994.

Reference 2

Reference Type:

publication

Title:

A 30-day Repeated Inhalation Toxicity Study of Potassium Amyl Xanthate (Z-6) in Laboratory Animals”,

Author:

Dow Chemical Company

Year:

1976

Bibliographic source:

Dow Chemical Company, Michigan, USA, 1976.

Reference 3

Reference Type:

review article or handbook

Title:

Full Public Report Sodium Ethyl Xanthate Priority Existing Chemical No. 5

Author:

Australian Government Publishing Service Canberra

Year:

1995

Bibliographic source:

Australian Government Publishing Service Canberra

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Potassium O-pentyl dithiocarbonate

EC Number:

220-329-5

EC Name:

Potassium O-pentyl dithiocarbonate

Cas Number:

2720-73-2

Molecular formula:

C6H12OS2.K

IUPAC Name:

potassium O-pentyl dithiocarbonate

Constituent 2

Reference substance name:

Potassium amyl xanthate

IUPAC Name:

Potassium amyl xanthate

Test material form:

aerosol dispenser: not specified

Remarks:

migrated information: aerosol

Test animals

Species:

dog

Strain:

Beagle

Sex:

male

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

air

Remarks on MMAD:

MMAD / GSD: Analysis of the particle size indicated that all the particles at the lower dose of 100 mg/m3 were less than 10μm in diameter while approximately 80% of the particles had a diameter of 10μm or less at a dose of 800 mg/m3. It is not possible to state from the description of the exposure method whether air flow was dynamic or static.

Details on inhalation exposure:

Animals were exposed to potassium amyl xanthate as an aqueous aerosol. Attempts at dust exposure were unsuccessful as potassium amyl xanthate is hygroscopic.
Animals were exposed to concentrations of 0, 100 and 800 mg/m3 of potassium amyl xanthate. These concentrations were equivalent to actual doses of 0, 23 and 252 mg/m3. Analysis of the particle size indicated that all the particles at the lower dose of 100 mg/m3 were less than 10μm in diameter while approximately 80% of the particles had a diameter of 10μm or less at a dose of 800 mg/m3. It is not possible to state from the description of the exposure method whether air flow was dynamic or static.
Exposure levels for the study were established by a preliminary experiment. In the preliminary experiment, three groups of 10 male Sprague-Dawley rats were exposed to concentrations of 0, 200 or 800 mg/m3 of potassium amyl xanthate, 6 hrs daily for 10 exposures in 2 weeks. No signs of toxicity were observed in animals exposed to a concentration of 200 mg/m3. Rats exposed to a concentration of 800 mg/m3 showed a statistically significant decrease in body weight after the fifth exposure. Recovery of the body weight occurred within 4 days and may not have been exposure related.
The only substance related adverse effect observed was a yellow-brown staining of the hair coat of the rats.
Overexposure of the animals exposed to a concentration of 800 mg/m3 occurred because of a technical problem in the aerosol generating apparatus.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

30-day

Frequency of treatment:

6 hrs daily, 5 days a week for a total of 20 exposures in 1 month

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/m³ air (nominal)

Remarks:

Control

Doses / concentrations 2

Dose / conc.:

100 mg/m³ air (nominal)

Remarks:

Doses / Concentrations:100 mg/m3Basis:nominal conc.

Doses / concentrations 3

Dose / conc.:

800 mg/m³ air (nominal)

Remarks:

Doses / Concentrations:800 mg/m3Basis:nominal conc.

No. of animals per sex per dose:

2

Control animals:

yes

Details on study design:

In the 30-day study, three groups of animals, each consisting of 10 male Swiss- Webster mice, 10 male Sprague-Dawley rats, 4 male New Zealand White rabbits and 2 male beagle dogs were exposed to either filtered room air or to concentrations of 100 or 800 mg/m3 of potassium amyl xanthate. Whole body exposure was for 6 hrs daily, 5 days a week for a total of 20 exposures in 1 month.
Ten mice of the 800 mg/m3 group died along with 5/6 replacement mice.
The animals were observed during the exposures and body weights were recorded three times a week throughout the experiment. Body weight data, organ to body weight ratios and clinical laboratory parameters were analysed statistically using analysis of variance and Dunnett’s test.

Most of the mice died when exposed to 800 mg/m3. Five of the 16 mice that died showed convulsions and hyperactivity prior to death. The adverse effects produced by the two doses of potassium amyl xanthate are shown in Table 1.

Positive control:

no data

Examinations

Observations and examinations performed and frequency:

Animals were exposed to concentrations of 0, 100 and 800 mg/m3 of potassium amyl xanthate. These concentrations were equivalent to actual doses of 0, 23 and 252 mg/m3. Analysis of the particle size indicated that all the particles at the lower dose of 100 mg/m3 were less than 10μm in diameter while approximately 80% of the particles had a diameter of 10μm or less at a dose of 800 mg/m3. It is not possible to state from the description of the exposure method whether air flow was dynamic or static.
Exposure levels for the study were established by a preliminary experiment. In the preliminary experiment, three groups of 10 male Sprague-Dawley rats were exposed to concentrations of 0, 200 or 800 mg/m3 of potassium amyl xanthate, 6 hrs daily for 10 exposures in 2 weeks. No signs of toxicity were observed in animals exposed to a concentration of 200 mg/m3. Rats exposed to a concentration of 800 mg/m3 showed a statistically significant decrease in body weight after the fifth exposure. Recovery of the body weight occurred within 4 days and may not have been exposure related.
The only substance related adverse effect observed was a yellow-brown staining of the hair coat of the rats.
Overexposure of the animals exposed to a concentration of 800 mg/m3 occurred because of a technical problem in the aerosol generating apparatus.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, the presence of tumours in the lungs, liver, kidneys, pancreas, spleen and any other organs were recorded.
HISTOPATHOLOGY: Yes, the lungs, liver, kidneys, pancreas, spleen and any other organs with tumours were sampled at necropsy.

Other examinations:

See table 1.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

See table 1.

Mortality:

no mortality observed

Description (incidence):

See table 1.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

See table 1.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

No statistically significant treatment related effects were observed.See table 1.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

No statistically significant treatment related effects were observed.See table 1.

Endocrine findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No significant differences were observed between the test and control groups. See table 1.

Effect levels

Dose descriptor:

LOEC

Effect level:

100 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Hepatotoxic effects

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Table 1 Results of repeated inhalation study with potassium amyl xanthate in laboratory animals

 

		Dogs (2 animals)	Rabbits (4 animals)	Rats (10 animals)	Mice (10,6 animals)
100 mg/m3	Eyes	No irritation	No irritation	No irritation	No irritation
	Nasal effects	No effects	No effects	No effects	No effects
	Hair coat	Yellow brown staining.	Progressive yellow brown staining	Yellow brown stainingof the hair coat of the rats.	No staining
	Other effects	Staining of the appendages and scrotum; ulceration of the skin in the scrotal region.	None	None	None
	Body weight	No change	No change	No change	No change
	Organ weight	No change	No change	No change	Higher liver to body weight ratio than controls
	Liver enzyme changes	Marked elevation of serum alanine aminotransferase and alkaline phosphatase activities	No change	No change	No change
	Histopathology changes	Hepatocellular degeneration, necrosis and inflammation	No treatment related change	No treatment related change	No treatment related change
	Deaths	None	None	None	None
800 mg/m3	Eye changes	Excessive lacrimation	Conjunctival redness	No irritation	No changes
	Nasal effects	None	None	Reddish nasal discharge	None
	Hair coat	Yellow brown staining	A more intense yellow brown	Yellow brown staining	No effects
	Skin	Ulceration of the skin	No effect	No effect	No effect
	Body weight	No effect	No effect	No effect	No effect
	Organ weight	No change	No change	Higher liver to body weight ratio than controls	Higher liver to body weight ratio than controls
	Liver enzyme changes	Marked elevations of serum alanine aminotransferase and alkaline phosphatase activities.	No changes	High serum alanine aminotransferase activity	No changes
	Histopathology changes	Hepatocellular degeneration, necrosis and inflammation	No changes	Microscopically visible granular degeneration	No changes
	Deaths	None	None	One, but not related to exposure	10 from the original group and 5/6 replacement animals died. Convulsions hyperactivity in 5/16 prior to death.

 

 

Applicant's summary and conclusion

Conclusions:

The results of this study indicate that potassium amyl xanthate has an adverse effect on the the liver in dogs. There were no treatment-related changes in the haematological or urinalysis values in any of the animals.