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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Carbon disulphide has been demonstrated to form during hydrolysis in gastric fluid.
Any oral toxicity on the xanthate needs to consider oral effects of carbon disulphide and the corresponding alcohol
Data access has been requested, but this summary is extracted from disseminated information published by ECHA
Further animal testing on the xanthate cannot be justified
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across: supporting information
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 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:
review article or handbook
Title:
Unnamed
Year:
2022

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
not specified
Remarks:
Pre-dates widespread introduction of GLP Data set considered valid
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Carbon disulphide
EC Number:
200-843-6
EC Name:
Carbon disulphide
Cas Number:
75-15-0
Molecular formula:
CS2
IUPAC Name:
carbon disulfide

Test animals

Species:
rat
Strain:
other: CD
Details on test animals or test system and environmental conditions:
Age 8 - 12 weeks at start of study

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Co-habitation 1:!
Duration of treatment / exposure:
Gestation day 6 to 15
Frequency of treatment:
Daily
Duration of test:
From gestation day 6 to 15
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Up to 27
Control animals:
yes, concurrent no treatment

Examinations

Maternal examinations:
Clinical signs daily after exposure
Ovaries and uterine content:
Yes
Blood sampling:
Not specified
Fetal examinations:
Yes; external, visceral, skeletal and head
Statistics:
As needed
Historical control data:
Not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Lethargy, ataxia, abnormal posture and rough coat
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female, mid dose
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decrease in body weight for highest doses
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Endocrine findings:
not examined
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increased liver weights in higher dose groups
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Other effects:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: Toxicological significance of maternal effects not specified

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Weight decrease in highest dose groups
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Reduced weights of litters at higher doses, mirroring maternal effect
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Across various dose levels and within historical control
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Across various dose levels and within historical control
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Across various dose levels and within historical control

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Abnormalities:
effects observed, non-treatment-related
Localisation:
other: Various changes - no obvious significance
Description (incidence and severity):
Various effects observed but within historical levels.

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Oral treatment produced dose-related maternal and foetal toxicity at 200 mg/kg bw/day or higher.
There was no increase in the incidence of malformed foetuses.