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Toxicological information

Neurotoxicity

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Administrative data

Description of key information

There are conclusive but not suffcient data for the classification of substance Sodium Isopropyl Xanthate (SIPX) with regard to Neurotoxicity.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
other: published data
Adequacy of study:
weight of evidence
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:
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)
Qualifier:
no guideline followed
Principles of method if other than guideline:
CS2 was administered by gavage to male rats for 12 w. In order to examine the mechanism of action of its neurotoxicity, cerebrum samples were analyzed for their content of six cytoskeletal proteins: NF-L, NF-M, NF-H (NF: neurofilaments), a-tubulin, b-tubulin, and b-actin by immunoblotting. Moreover, neurological tests were performed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Experimental Animal Center of Shandong University
- Weight at study initiation: 180-200 g
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): no
- Concentration in vehicle: 3 ml/kg
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
12 w
Frequency of treatment:
daily, 5 d/w
Remarks:
Doses / Concentrations:
0, 300, and 500 mg/kg bw
Basis:
other: treatment by gavage
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Observations and clinical examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: twice per week

Specific biochemical examinations:
Nerve homogenates (cerebrum) were centrifuged at 100,000 g for 1 h to yield a high-speed pellet (P) and a high-speed supernatant (S). According to previous experiments, the P fraction consists of polymerized triplet proteins and represents the triton-insoluble filamentous cytoskeletal network . The high-speed supernatant (S) likely contains tritonsoluble NF (neurofilament) proteins in the form of intermediate heterotetramers and monomers that represent the mobile population of exchangeable NF (neurofilament) proteins . Protein concentration of two fractions was measured with the use of a Protein assay Kit.

In order to investigate alterations of NF subunits monoclonal antibodies for NF-H, NF-M, and NF-L were used by immunoblotting.
Neurobehavioural examinations performed and frequency:
NEUROLOGICAL TESTING: performed twice per week; involving gait scores and rotarod performance. To measure gait abnormalities, rats were placed in an open field, and were observed for 3 min. Post-observation, a gait score was given from 1 to 4 corresponding to 1=a normal, unaffected gait; 2=a slightly abnormal gait (hindlimbs show uncoordinated placement, exaggerated or overcompensated movements, or are splayed slightly, walks on tiptoes); 3=moderately abnormal gait (obvious movement abnormalities characterized by markedly splaying hindlimbs, ataxia, swaying, rocking, lurching, stumbling); 4=severely abnormal gait (flat foot walk, hindlegs flat on surface, crawling, or unable to support weight). In the rotarod performance, rats were placed on an accelerating rotarod, and the retention time was recorded.
Statistics:
Mann-Whitney U-test, Kruskal-Wallis H-test, one-way analysis of variance, LSD's post hoc tests (P<0.05)
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
Clinical biochemistry findings:
effects observed, treatment-related
Behaviour (functional findings):
effects observed, treatment-related
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Details on results:
Exposure to CS2 resulted in decrease of body weight gain, progressive gait abnormalities and reductions in retention time on the accelarating rotarod. At the end of the exposure, most of the animals showed moderately abnormal gait. At the end of the week 12, rats treated with 300 mg/kg CS2 showed much less retention times than the control animals, while rats treated with 500 mg/kg CS2 hardly kept any retention on the ratorod.

Biochemical examinations
pellet(P): significant decrease in NF-H, NF-M and NF-L levels at both exposure doses, compared to the controls. Protein levels of alpha-tubulin remained at control levels, while these of beta-tubulin decreased significantly. The protein levels of beta-actin remained unchanged.
supernatant (S): significant decrease in NF-H, NF-M and NF-L levels at both exposure doses, compared to the controls. Both alpha- and beta-tubulin were increased significantly, indicating a possible translocation of proteins from one subcellular fraction to the other. A significant increase was observed in the levels of beta-actin only in the rats treated with 500 mg/kg bw.
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decreased body weight, progressive gait abnormalities, neurofilamentous accumulations in the cerebral cortex
Remarks on result:
other:
Conclusions:
Carbon disulfide exposure by gavage in rats (300 and 500 mg/kg bw) resulted in neurological effects, i.e. abnormal gait and reductions in retention time on the accelarating rotarod, as well as in significant reductions of neurofilaments (NF) subunits and increase of microtubules and microfilaments subunits, in cerebral cortex homogenates. The authors associate the changes in the NFs cerebrum proteins with the CS2 treatment, suggesting this as a possible mechanism inducing neuropathy.
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)
Executive summary:

What follows is the abstract of the original publication with slight modifications

To investigate the mechanism of carbon disulfide-induced neuropathy, male wistar rats were administrated by gavage at dosage of 300 or 500 mg/kg carbon disulfide, five times per week for 12 weeks. By the end of the exposure, the animals produced a slight or moderate level of neurological deficits, respectively. Cerebrums of carbon disulfide-intoxicated rats and their age-matched controls were Triton-extracted and centrifuged at a high speed (100,000 X g) to yield a pellet fraction of neurofilament (NF) polymer and a corresponding supernatant fraction, which presumably contained mobile monomer. Then, the contents of six cytoskeletal protein (NF-L, NF-M, NF-H, alpha-tubulin, beta-tubulin, and beta-actin) in both fractions were determined by immunoblotting. Results showed that the contents of the three neurofilament subunits in the pellet and the supernatant fraction decreased significantly regardless of dose levels (P<0.01). As for microtubule proteins, in the pellet fraction of cerebrum, the levels of alpha-tubulin and beta-tubulin demonstrated some inconsistent changes. However, in the supernatant fractions, the content of alpha-tubulin and beta-tubulin increased significantly in both two dose groups (P<0.01). In comparison to neurofilament and tubulin proteins, the content of beta-actin changed less markedly, only the supernatant fraction of the high dose group displayed significant increase (P < 0.01), but the others remained unaffected. These findings suggested that the changes of cytoskeleton protein contents in rat cerebrum were associated with the intoxication of carbon disulfide, which might be involved in the development of carbon disulfide neurotoxicity.

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

Effect on neurotoxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: sub-chronic inhalation
Type of information:
other: published data
Adequacy of study:
weight of evidence
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:
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)
Qualifier:
no guideline followed
Principles of method if other than guideline:
The aim of the study was to examine the morphological progression and dose response of CS2 distal axonopathy in the muscular branch of the posterior tibial nerve (MBPTN) and spinal cord. Rats were exposed to various concentrations of CS2 by inhalation for various time points. This publication is only one part of a whole study that aimed at investigating CS2 neurotoxicity in a coordinated way (several endpoints included); see below for details.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC)
- Age at study initiation: 8-9 weeks
- Housing: individually in wire-mesh cages within the exposure chambers
- Diet: ad libitum, only during non-exposure times
- Water: ad libitum
- Acclimatation period: 10-14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 49.1
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Data taken from Sills et al. (1998a, Carbon disulfide neurotoxicity in rats: I. Introduction and study design. NeuroToxicology 19 (1): 83-88)

CS2 was vaporized mixed with conditioned air and delivered to the chambers.
- Air flow rate: 4 l/min
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Monitored every 15 min with infrared spectrophotometers; maintained at the 3% of the targeted concentrations throughout the study.
Duration of treatment / exposure:
6 h/d for 2, 4, 8 or 13 w
Frequency of treatment:
daily, 5 d/w
Remarks:
Doses / Concentrations:
0, 50, 500, 800 ppm (0, 156, 1558, 2493 mg/m3)
Basis:
nominal conc.
No. of animals per sex per dose:
9 (in the 13 week study an additional 9 animals per dose/sex were included)
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: according to Sill et al. (1998a; Carbon disulfide neurotoxicity in rats: I. Introduction and study design. NeuroToxicology 19 (1): 83-88) the exposure concentrations were selected based on previous studies (Gottfried et al., 1985) demonstrating that metabolic saturation occurs at approximately 600 ppm CS2. Concentrations above (800 ppm) and below (500 ppm) metabolic saturation were selected for use, as well as, a concentration close to the current TLV of 10 ppm (50 ppm).
Sacrifice and (histo)pathology:
- Number of animals sacrificed: all
- Procedures for perfusion: rats were ansthetized with sodium pentobarbital containing heparin, and perfused through the heart with 4% phosphate buffered paraformaldehyde followed by 4% phosphate buffered glutaraldehyde pH 7.4
- Number of animals perfused: all
Gross examinations were performed
- Tissues evaluated: sciatic nerve, muscular branch of the posterior tibial nerve and caudal tail nerve, multiple levels of the spinal cord including C1 and C2, and L1 and L2 (light & electron microscopy), whole brain (cerebrum, cerebellum, midbrain), heart, aorta, lung, trachea, liver, kidneys, nasal cavity, testes, epididymis, ovaries, oviducts, uterus and vagina

For sciatic nerve, muscular branch of the posterior tibial nerve and caudal tail nerve, multiple levels of the spinal cord including C1 and C2, and L1 and L2
- Type of staining: 1% toluidinine blue (light microscopy), lead citrate and uranyl acetate (electron microscopy)
- Thickness: 1 micron
- Embedding media: Epon resin

All the other organs except for testes/epididymes, were trimmed, embedded in paraffin, sectioned and stained with hematoxylin and eosin (H&E). The testes and epididymes were embedded in glycol methacrylate and stained with periodic acid shift and H&E.
Other examinations:
All the other examinations can be seen in the relevant seperate study entry (see below for details, section 'any other information on materials and methods incl. tables').
Statistics:
Fischer's exact test
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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
Clinical biochemistry findings:
not specified
Behaviour (functional findings):
not specified
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
effects observed, treatment-related
Details on results:
NEUROPATHOLOGY
PNS: The muscular branch of the posterior tibial nerve (MBPTN) was the most sensitive to CS2 toxicity, compared to the sciatic and caudal tail nerve. Animals in the exposure group of 800 ppm had focal to multifocal giant axonal swelling in the MBPTN starting from the 8th w, that evolved from minimal to moderate from week 8 to 13. Degeneration and regeneration were observed at 13 w. Axonal swelling or other morphological changes were not detected at weeks 2 and 4 or at lower concentrations. Ultrastractural examinations revealed accumulation of 10 nm neurofilaments in swollen axons. The swollen axons were usually accompanied by myelin sheath thinning (reduced number of myelin lamellae).

CNS: Similarly to the MBPTN, axonal swelling was prominent at 8 w in the spinal cord segments, but at both 500 and 800 ppm exposure levels. By 13 w it progressed to moderate. Lumbar spinal cord swelling was more pronounced, compared to the cervical cord segments. The swollen axons of the lumbar cord had accumulated 10 nm neurofilaments. Axonal swelling was not observed at weeks 2 and 4 or at 50 ppm.
Dose descriptor:
NOAEC
Effect level:
50 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no axonal swelling in the muscular branch of the porterior tibial nerve and spinal cord
Remarks on result:
other:
Dose descriptor:
NOAEC
Effect level:
156 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no axonal swelling in the muscular branch of the porterior tibial nerve and spinal cord
Remarks on result:
other:

OTHER FINDINGS Lesions related to CS2 exposure were not detected in the heart, brain, aorta, lung, trachea, liver, kidneys, nasal cavity, testes, epididymis, ovaries, oviducts, uterus and vagina.

Conclusions:
Lesions of axonal swelling were observed in the MBPTN after 8 w of exposure to 800 ppm, and in the spinal cord after 8 w of exposure to 500 and 800 ppm. No lesions related to CS2 exposure were detected in the heart, brain, aorta, lung, trachea, liver, kidneys, nasal cavity, testes, epididymis, ovaries, oviducts, uterus and vagina at 50 ppm.
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)
Executive summary:

The aim of the study was to examine the morphological progression and dose response of CS2 distal axonopathy in the muscular branch of the posterior tibial nerve (MBPTN) and spinal cord. For this reason, male and female Fischer 344 rats were exposed to 0, 50, 500, 800 ppm (0, 156, 1558, 2493 mg/m3) of CS2, 6 h/d, 5 days per week, for 2, 4, 8 or 13 w, via inhalation. At 8 w axonal swelling was observed in the MBPTN of animals exposed at 800 ppm, that progressed to more severe at 13 w. Similarly, axonal swelling was seen in the cervical and lumpar spinal cord, after 8 w, but at both high exposure concentrations. Swelling was accompanied by thinning of the myelin sheath and accumulation of 10 nm neurofilaments. No lesions related to CS2 exposure were detected in the heart, brain, aorta, lung, trachea, liver, kidneys, nasal cavity, testes, epididymis, ovaries, oviducts, uterus and vagina.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
156 mg/m³
Study duration:
subchronic
Species:
rat

Effect on neurotoxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
other: published data
Adequacy of study:
weight of evidence
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:
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)
Qualifier:
no guideline followed
Principles of method if other than guideline:
CS2 was administered by gavage to male rats for 12 w. In order to examine the mechanism of action of its neurotoxicity, cerebrum samples were analyzed for their content of six cytoskeletal proteins: NF-L, NF-M, NF-H (NF: neurofilaments), a-tubulin, b-tubulin, and b-actin by immunoblotting. Moreover, neurological tests were performed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Experimental Animal Center of Shandong University
- Weight at study initiation: 180-200 g
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): no
- Concentration in vehicle: 3 ml/kg
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
12 w
Frequency of treatment:
daily, 5 d/w
Remarks:
Doses / Concentrations:
0, 300, and 500 mg/kg bw
Basis:
other: treatment by gavage
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Observations and clinical examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: twice per week

Specific biochemical examinations:
Nerve homogenates (cerebrum) were centrifuged at 100,000 g for 1 h to yield a high-speed pellet (P) and a high-speed supernatant (S). According to previous experiments, the P fraction consists of polymerized triplet proteins and represents the triton-insoluble filamentous cytoskeletal network . The high-speed supernatant (S) likely contains tritonsoluble NF (neurofilament) proteins in the form of intermediate heterotetramers and monomers that represent the mobile population of exchangeable NF (neurofilament) proteins . Protein concentration of two fractions was measured with the use of a Protein assay Kit.

In order to investigate alterations of NF subunits monoclonal antibodies for NF-H, NF-M, and NF-L were used by immunoblotting.
Neurobehavioural examinations performed and frequency:
NEUROLOGICAL TESTING: performed twice per week; involving gait scores and rotarod performance. To measure gait abnormalities, rats were placed in an open field, and were observed for 3 min. Post-observation, a gait score was given from 1 to 4 corresponding to 1=a normal, unaffected gait; 2=a slightly abnormal gait (hindlimbs show uncoordinated placement, exaggerated or overcompensated movements, or are splayed slightly, walks on tiptoes); 3=moderately abnormal gait (obvious movement abnormalities characterized by markedly splaying hindlimbs, ataxia, swaying, rocking, lurching, stumbling); 4=severely abnormal gait (flat foot walk, hindlegs flat on surface, crawling, or unable to support weight). In the rotarod performance, rats were placed on an accelerating rotarod, and the retention time was recorded.
Statistics:
Mann-Whitney U-test, Kruskal-Wallis H-test, one-way analysis of variance, LSD's post hoc tests (P<0.05)
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
Clinical biochemistry findings:
effects observed, treatment-related
Behaviour (functional findings):
effects observed, treatment-related
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Details on results:
Exposure to CS2 resulted in decrease of body weight gain, progressive gait abnormalities and reductions in retention time on the accelarating rotarod. At the end of the exposure, most of the animals showed moderately abnormal gait. At the end of the week 12, rats treated with 300 mg/kg CS2 showed much less retention times than the control animals, while rats treated with 500 mg/kg CS2 hardly kept any retention on the ratorod.

Biochemical examinations
pellet(P): significant decrease in NF-H, NF-M and NF-L levels at both exposure doses, compared to the controls. Protein levels of alpha-tubulin remained at control levels, while these of beta-tubulin decreased significantly. The protein levels of beta-actin remained unchanged.
supernatant (S): significant decrease in NF-H, NF-M and NF-L levels at both exposure doses, compared to the controls. Both alpha- and beta-tubulin were increased significantly, indicating a possible translocation of proteins from one subcellular fraction to the other. A significant increase was observed in the levels of beta-actin only in the rats treated with 500 mg/kg bw.
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: decreased body weight, progressive gait abnormalities, neurofilamentous accumulations in the cerebral cortex
Remarks on result:
other:
Conclusions:
Carbon disulfide exposure by gavage in rats (300 and 500 mg/kg bw) resulted in neurological effects, i.e. abnormal gait and reductions in retention time on the accelarating rotarod, as well as in significant reductions of neurofilaments (NF) subunits and increase of microtubules and microfilaments subunits, in cerebral cortex homogenates. The authors associate the changes in the NFs cerebrum proteins with the CS2 treatment, suggesting this as a possible mechanism inducing neuropathy.
Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)
Executive summary:

What follows is the abstract of the original publication with slight modifications

To investigate the mechanism of carbon disulfide-induced neuropathy, male wistar rats were administrated by gavage at dosage of 300 or 500 mg/kg carbon disulfide, five times per week for 12 weeks. By the end of the exposure, the animals produced a slight or moderate level of neurological deficits, respectively. Cerebrums of carbon disulfide-intoxicated rats and their age-matched controls were Triton-extracted and centrifuged at a high speed (100,000 X g) to yield a pellet fraction of neurofilament (NF) polymer and a corresponding supernatant fraction, which presumably contained mobile monomer. Then, the contents of six cytoskeletal protein (NF-L, NF-M, NF-H, alpha-tubulin, beta-tubulin, and beta-actin) in both fractions were determined by immunoblotting. Results showed that the contents of the three neurofilament subunits in the pellet and the supernatant fraction decreased significantly regardless of dose levels (P<0.01). As for microtubule proteins, in the pellet fraction of cerebrum, the levels of alpha-tubulin and beta-tubulin demonstrated some inconsistent changes. However, in the supernatant fractions, the content of alpha-tubulin and beta-tubulin increased significantly in both two dose groups (P<0.01). In comparison to neurofilament and tubulin proteins, the content of beta-actin changed less markedly, only the supernatant fraction of the high dose group displayed significant increase (P < 0.01), but the others remained unaffected. These findings suggested that the changes of cytoskeleton protein contents in rat cerebrum were associated with the intoxication of carbon disulfide, which might be involved in the development of carbon disulfide neurotoxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEL
7.5 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
For dermal exposure we taken that:
-the average weight of rat is 250 g (200 -300 g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.008 kg
 
corrected dermal LOAEL=    oral LOAEL
                                   300 mg/kg bw/dx 0.025 kg =                   
 LOAELrat     7.5 mg/kg bw/day

Additional information

oral exposure

Carbon disulfide exposure by gavage in rats (300 and 500 mg/kg bw) resulted in neurological effects, i.e. abnormal gait and reductions in retention time on the accelarating rotarod, as well as in significant reductions of neurofilaments (NF) subunits and increase of microtubules and microfilaments subunits, in cerebral cortex homogenates. The authors associate the changes in the NFs cerebrum proteins with the CS2 treatment, suggesting this as a possible mechanism inducing neuropathy.

Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)

LOAEL=300 mg/kg bw day

dermal exposure

For dermal exposure we taken that:

-the average weight of rat is 250 g (200 -300 g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.008 kg

 

corrected dermal LOAEL=    oral LOAEL

                                   300 mg/kg bw/dx 0.025 kg =                   

 LOAELrat     7.5 mg/kg bw/day

 

Inhalation exposure:

The aim of the study of Sills RC, et al.1998 was to examine the morphological progression and dose response of CS2 distal axonopathy in the muscular branch of the posterior tibial nerve (MBPTN) and spinal cord. For this reason, male and female Fischer 344 rats were exposed to 0, 50, 500, 800 ppm (0, 156, 1558, 2493 mg/m3) of CS2, 6 h/d, 5 days per week, for 2, 4, 8 or 13 w, via inhalation. At 8 w axonal swelling was observed in the MBPTN of animals exposed at 800 ppm, that progressed to more severe at 13 w. Similarly, axonal swelling was seen in the cervical and lumpar spinal cord, after 8 w, but at both high exposure concentrations. Swelling was accompanied by thinning of the myelin sheath and accumulation of 10 nm neurofilaments. No lesions related to CS2 exposure were detected in the heart, brain, aorta, lung, trachea, liver, kidneys, nasal cavity, testes, epididymis, ovaries, oviducts, uterus and vagina.

The NOAEC was 156 mg/m3 based on the no axonal swelling in the muscular branch of the porterior tibial nerve and spinal cord.

 Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates.Sodium Isopropyl Xanthate (SIPX) readily decomposes to carbon disulphide, especially in the presence of moisture/water. Therefore, the health effects of carbon disulphide (CS2) need to be considered in the assessment of Sodium Isopropyl Xanthate (SIPX)

 

 

 

Justification for classification or non-classification

There are conclusive but not suffcient data for the classification of substance Sodium Isopropyl Xanthate (SIPX) with regard to Neurotoxicity.