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Description of key information

There is available low quality repeated oral toxicity study conducted for the analogue substance, potassium butyl xanthate, showing LOAEL of 10 mg/kg bw/day. The study is considered not reliable, since the documentation is not sufficient for assessment.
The intrinsic properties of potassium isoamyl xanthate are related to the most hazardous degradation product; carbon disulphide. The estimated concentrations of CS2 in the water solutions are below 0.2 % and estimated CS2 air concentrations much below 15 ppm.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was regarded not reliable since there is not enough data for assessment. Read-across justification: Target substance belongs into the group of substances called xanthates. The xanthates are generally prepared from the reaction of the alkoxide, which reacts with carbon disulphide to give the xanthate. These substances contain common functional group which is dithiocarbonate (-OCSS-). Though they are structural analogues with the target substance. All these analogue substances are also used in similar use application as water solutions. All xanthates decompose in the presence of water. In neutral to alkaline media, they will release carbon disulphide, particular alcohol(s) and carbonates and dithiocarbonates. Carbon disulphide is the major and the most volatile and the most hazardous decomposition product of xanthates. It is also more toxic to human health than the target substance. As the xanthates can be considered as a group of substances which have structural similarity and similar behaviour in contact with water and in the physiological processes, their irritation as well as acute and systemic adverse effects to human health are similar. Therefore, and in order to avoid the unnecessary animal testing, the read-across data from the analogue xanthates is used to evaluate the irritation, and short term and/or long-term toxicological effects of the target substance. As the target substance is an unstable compound, the apparent toxicity reflects to the toxicity of the degradation products. The selection of the most critical degradation products for the hazard assessment are based on the known decomposition reaction of the target substance and based on the physicochemical properties and toxicological properties of the degradation products. The adverse effects through inhalation route are not relevant for the substance itself, which is a solid non-volatile pellet form substance. However, the most serious human health hazards are related to CS2 released from the target substance. Therefore, the formation of carbon disulphide by decomposition is the driving force for human health hazard assessment via inhalation and taken into account in DNEL derivation and in the exposure assessment of the target substance.
Reference:
Composition 0
Principles of method if other than guideline:
Potassium butyl xanthate was administered orally (10mg/kg) to rats for 4 months.
GLP compliance:
no
Test material information:
Composition 1
Species:
rat
Route of administration:
oral: gavage
Vehicle:
not specified
Duration of treatment / exposure:
4 months
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
10 mg/kg
Basis:
actual ingested
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
From the 6-7th week, the animals of the first two groups developed signs of intoxication. Apathy, drowsiness, limited movement, rapid breathing, cyanotic eye mucous membranes, fur loss, seizures, and paresis and paralysis of the limbs were all noted, and many rats lacked reaction to pain stimulus. Some of the animals died during and after the experiments. Some animals died during the administration.

BODY WEIGHT AND WEIGHT GAIN
A statistically significant (P≤0.05) weight loss (of 23%),

CLINICAL CHEMISTRY
an increase in blood sugar (of 72-85%) and cholesterol (of 49%) in the blood and in sulfhydryl groups of serum proteins (from 70% to more than double), a reduction in the albumin/globulin ratio, a change in the fractional composition of serum proteins (hyperglobulinemia with dominant β fraction). Also, the animals from these groups showed significant changes in the metabolism of a series of mineral substances, namely zinc, copper, manganese, magnesium, molybdenum, titanium, silicon, phosphorus, iron, aluminium, and calcium. In some organs the content of some of these elements increased, while in other organs it decreased. The most typical changes were in the metabolism of the microelements Zn and Cu: they decreased in all organs, and there was a parallel increase in their excretion from the body.

NEUROBEHAVIOUR
A change in the ability of the central nervous system to register subthreshold impulses.

GROSS PATHOLOGY
The main changes in the nervous system are severe vascular damage in various parts of the brain, dystrophic changes in the nerve cells of the cortex, basal ganglia, thalamohypothalamic area and brain stem in the form of swelling with severe vacuolization of protoplasm in individual nerve cells and karyolysis and cytolysis with the formation of ghost cells. Dystrophic changes in the form of swelling and vacuolization of the protoplasm of nerve cells and the death of individual neurons were found in nerve cells of the anterior horn of the spinal cord. Local myelin disintegration on Nissl bodies and bead-like deformation of axons were observed in peripheral nerves. The latter coincides with clinical manifestations of paralysis.
Dystrophic changes in the liver and kidneys are pronounced.
Dose descriptor:
NOAEL
Effect level:
< 10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Critical effects observed:
not specified
Conclusions:
Potassium butyl xanthate was administered orally at dose level of 10 mg/kg/day in rats. Mortality and severe adverse effects were observed during administration. Thus, the NOAEL is determined to be < 10mg/kg/day.
Executive summary:

The subacute toxicity study was conducted for potassium butyl xanthate, the analogue substance of potassium isoamyl xanthate. This study showed pathological and morphological changes in several tissues. Severe vascular changes were observed in the brain and spinal cord, dystrophic changes were identified in the nerve cells of various parts of the brain and in the anterior horn of the spinal cord, and gross morphological changes were found in the peripheral nerves. Animals also developed dystrophic changes in the liver (steatosis) and in the kidneys (proteinosis of convoluted tubule epithelium).

 

Animal developed a series of changes in physiological and biochemical indicators, which are largely similar to those from carbon disulfide intoxication. The following effects were obseved: weight loss, an increase in oxygen consumption, a change in the ability of the central nervous system to register subthreshold impulses, an increase in blood sugar and cholesterol in the blood, as well as the content of sulfhydryl groups of serum proteins (hyperglobulinemia with dominant β fraction and a reduction in the albumin/globulin ratio), and changes in the metabolism of elements Zn, Cu, Mn, Mo, Mg, Ti, P, Si, Fe, Al and Ca.

The result of this study is used as a weight of evidence in hazard assessment.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated oral toxicity

The weight of evidence approach is used to determine the hazard caused by repeated oral administration of potassium isoamyl xanthate. Since there is no data available from the substance itself, the relevant data from the analogue substance, potassium butyl xanthate was assessed. The read-across justification is presented in the Annex I of this CSR.

The sub-chronic oral study by Babayan (1968) was regarded not reliable since no details on the test substance composition were available and no possible impurities in the test substance were reported. Since the available data is not convincing for expert judgement and a good quality data is lacking, there is currently no need to classify this substance for repeated oral toxicity.

Potassium butyl xanthate was administered orally (10 mg/kg) to rats for 4 months. During this period some animals died. This study showed pathological and morphological changes in several tissues. Severe vascular changes were observed in the brain and spinal cord, dystrophic changes were identified in the nerve cells of various parts of the brain and in the anterior horn of the spinal cord. Furthermore, gross morphological changes were found in the peripheral nerves. Animals also developed dystrophic changes in the liver (steatosis) and in the kidneys (proteinosis of convoluted tubule epithelium).

Animals developed a series of changes in physiological and biochemical indicators, which are largely similar to those from carbon disulfide intoxication. The following effects were obseved: weight loss, an increase in oxygen consumption, a change in the ability of the central nervous system to register subthreshold impulses, an increase in blood sugar and cholesterol in the blood, as well as the content of sulfhydryl groups of serum proteins (hyperglobulinemia with dominant β fraction and a reduction in the albumin/globulin ratio), and changes in the metabolism of elements Zn, Cu, Mn, Mo, Mg, Ti, P, Si, Fe, Al and Ca.

Repeated inhalation toxicity

Inhalation route is not likely route of human exposure since potassium isoamyl xanthate is used as pellets. However, the substance in the presence of moisture decomposes to carbon disulphide. Carbon disulphide is a volatile and the most hazardous decomposition product of potassium isoamyl xanthate. Thus the toxicity of the CS2 after repeated exposure via inhalation is discussed below.

This substance is hydrolytically unstable. As it is used in water solutions the systemic adverse effects are related to the main degradation products. It will decompose in water releasing mainly carbon disulphide and particular alcohols (3-methyl-butan-1-ol and pentan-1-ol). The decomposition rate is dependent on the pH, temperature and the concentration of the substance in water solutions. The loss of xanthates for 10 %, 25 % and 40 % water solutions to volatile degradation products at 20 deg. C is measured to be 1.1 to 0.5 %, and at 30 deg. C 2.7 to 2.0 %, respectively. The release of CS2 during the storage from the 25 % water solution is estimated to be below 0.2 % per day at 20 °C and 30 °C (Aeroxanthate handbook 1972). Carbon disulphide as the major degradation product has the harmonized classification for Repro 2 with SCL of 1 % and for STOT-RE1 (SCL for STOT RE 2 is 0.2% and SCL for STOT-RE 1 is 1% ). Since CS2 is the most volatile and the most hazardous degradation product, it is the driving force for the hazard assessment of the target substance. Therefore, the exposure to CS2 via inhalation has been taken into account in the quantitative exposure assessment (sections 9&10 of CSR). The exposure assessment was done based on the monitoring data from end user sites as well as based on the modelled exposure estimates. According to the results of the assessment, the risks were considered controlled when appropriate OCs and RMMs with PPEs and safety practices are applied.

According to the risk characterisation the amounts of CS2 released from the substance do not trigger the target substance to be classified for the hazard class STOT-RE, and the CSA does not indicate to further investigate the repeated dose toxicity of the target substance.

Repeated inhalation toxicity studies have investigated the effects of CS2 on the nervous system. Medium and long-term exposure of rats to CS2 levels between 253 ppm (800 mg/m3) and 791 ppm (2500 mg/m3) has been associated with reduction in the nerve conduction velocity in the peripheral nerves and spinal cord (Environment Canada and Health Canada, 2000). This effect was often accompanied in later stages by neurological impairment and atrophy of the hind limbs and was only partially reversible upon cessation of exposure. Reduction in the nerve conduction velocity have also been observed in central nervous system and in the optic pathway in rats exposed to 791 ppm (2500 mg/m3) for periods of 11-15 weeks (Rebert and Becker, 1986; Hirata et al., 1992 cited in Environment Canada and Health Canada, 2000). In the latter study, there was also a transient increase in the latency of some components of the brainstem auditory evoked potential at 198 ppm (625 mg/m3) (Hirata et al., 1992).

The reductions in nerve conduction velocity observed in animal studies are accompanied by characteristic histopathological lesions in the axon. In a number of studies, rats exposed to between 253 ppm (800 mg/m3) and 791 ppm (2500 mg carbon disulfide/m3) for between 3 and 15 months developed an axonopathy in the peripheral nerves and/or spinal cord (Environment Canada and Health Canada, 2000).

The majority of the available epidemiological studies are of workers in the viscose rayon industry, in which workers are exposed to airborne carbon disulfide. Neurophysiological effects on both the peripheral and central nervous systems, as well as behavioural and neuropathological effects, have been reported in a number of cross-sectional studies of workers exposed to carbon disulfide in the viscose rayon industry. The most common observations are of effects on the peripheral nervous system, most often characterized by reduced conduction velocity in the motor and, in some instances, sensory nerves, and generally most pronounced in the more distal portions of the nervous system (e.g., in the lower limbs).

Based on the results of studies of workers exposed to carbon disulfide, the nervous system appears to be the critical target for carbon disulfide induced toxicity, manifested most often by reduced conduction velocity in the peripheral nerves and impaired performance in psychomotor testing (Environment Canada and Health Canada, 2000). Other effects for which there is considerable weight of evidence in humans exposed to carbon disulfide include alterations in serum lipids and blood pressure that are associated with increased risk of cardiovascular disease, systemic eye pathologies such as colorvision and damage to the blood vessels of the retina, and with higher exposures increased mortality from heart disease. No evidence of carcinogenicity has been observed in limited epidemiological studies.

Repeated dermal toxicity

Dermal route is not considered to be relevant exposure route, as skin contact is not likely during the production and use of the test substance because of adequate RMMs in use (see sections 9&10 of CSR).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
There are no studies conducted for the target substance. The selected subchronic study was conducted for the analogue substance, potassium butyl xanthate.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Not likely exposure route for the substance itself which is solid. The hazards of the most critical decomposition product (CS2) are taken into account in HA and CSA as it is released from the target substance in use applications from xanthate water solutions .

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Not likely exposure route for the substance itself which is solid. The hazards of the most critical decomposition product (CS2) are taken into account in HA and CSA as it is released from the target substance in use applications from xanthate water solutions .

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Not likely exposure route.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Not likely exposure route.

Justification for classification or non-classification

The sub-chronic oral study by Babayan (1968) performed for the read-across substance was regarded not reliable since the available data is not convincing for expert judgement. Thus, there is currently no need to classify potassium isoamyl xanthate for repeated oral toxicity in accordance with the criteria of CLP Regulation 1272/2008 and the EU directive 67/548/EEC.

The intrinsic properties of potassium isoamyl xanthate are related to the most hazardous degradation product; carbon disulphide. Based on the observations made after the subchronic carbon disulphide exposures in humans by inhalation route, exposure calculations and measured concentrations in mining processes there is no need for classification of the target substance in accordance with the criteria of CLP Regulation 1272/2008 and the EU directive 67/548/EEC.