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REACH

S-allyl O-pentyl dithiocarbonate

EC number: 220-977-9 | CAS number: 2956-12-9

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Link to relevant study record(s)

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

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:

Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Objective of study:

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

This toxicokinetics publication is only one part of a comprehensive study that aimed at investigating CS2 neurotoxicity in a coordinated way (several endpoints included); see below for details. Although the methods described do not follow the standard guidelines for toxicokinetic studies, the study gives reliable information about the toxicokinetics of CS2, in particular absorption, elimination and distribution and the urnary excretion of the metabolite used for biomonitoring purposes, viz., TTCA. The publication is the second of a series of 3 and many exerimental details are provided in Sills et al. (1998a, Carbon disulfide neurotoxicity in rats: I. Introduction and study design. NeuroToxicology 19 (1): 83-88).

GLP compliance:

not specified

Remarks:

It is not customary to refer to GLP in publications in peer-reviewed scientific pape

Radiolabelling:

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

Data taken from Sills et al. (1998a, Carbon disulfide neurotoxicity in rats: I. Introduction and study design. NeuroToxicology 19 (1): 83-88)

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:

other: intravenous injection and inhalation (vapour)

Vehicle:

other: mixed with air in the inhalation studies; mixture of emulphor, ethanol and water (1:1:8)

Duration and frequency of treatment / exposure:

3 different exposures regimens were applied: 1. single intravenous injection, 2. single exposure by inhalation: 180 min, and 3. repeated exposure by inhalation: 6 h/d, 5 d/w, for 2, 4, 8 or 13 w.

Remarks:

Doses / Concentrations:
intravenous injection: 50 mg/kg;
single inhalation exposure: 180 min nose only to 50 ppm, 500 ppm and 800 ppm (156, 1558, 2493 mg/m3);
repeated inhalation exposure:0, 50 ppm, 500 ppm and 800 ppm (156, 1558, 2493 mg/m3).

No. of animals per sex per dose / concentration:

intravenous injection: 3 males
single inhalation exposure: 2 groups of 6/sex/dose
repeated inhalation exposure: 6/sex/dose

Control animals:

yes, sham-exposed

Positive control reference chemical:

Details on study design:

Dose selection rationale: according to Sills 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 TLV of 10 ppm (50 ppm).

The jugular vein of the rats was cannulated in the experiments were a single inhalation exposure or intravenous injection was applied.

Details on dosing and sampling:

INTRAVENOUS INJECTION
Urine was collected for 24 h after injection. 200 microL blood samples were taken at 3, 5, 10, 20, 40, 60, 120 and 240 min after injection.
SINGLE INHALATION EXPOSURE
Blood was sampled for one group 4, 8, 15, 30, 60 and 180 min after the start of exposure and 4, 8, and 15 min postexposure; for the other group 60 and 180 min after the start of exposure and 30, 60, 90, 120, 240, and 300 min postexposure.
REPEATED INHALATION EXPOSURE
Urine was collected for 18 h immediately after the penultimate exposure
Blood (200 microL) was collected from the tail vein during the last hour of the last 6 h nose-only exposure.
CS2 ANALYSIS IN BLOOD
Head-space analysis by means of GC with flame photometric detector; limit of detection: 1 to 2 microg/mL.
TTCA ANALYSIS IN URINE
Reversed-phase LC after acidification and ethyl acetate extraction of the urine.

Details on absorption:

See below under "Any other information on results incl. tables"

Details on distribution in tissues:

See below under "Any other information on results incl. tables"

Details on excretion:

See below under "Any other information on results incl. tables"

Metabolites identified:

yes

Details on metabolites:

TTCA (1-thiothiazolidine-4-carboxylic acid), a known metabolite of CS2, which is used for biomonitoring purposes, was determined in the urine of the rats.

INTRAVENOUS INJECTION

The blood concentrations were below the level of detection after 120 min. A two-compartment model with first order elimination from the central compartment was developed. The following equation was developed by means of a least-squres fit of the blood concentration. C(t) = 44*e^-0.52t + 9.8*e^-0.029t. Kinetics constants were calculated with this equation. The apparent volume of distribution central and total were 0.9 L/kg and 4.2 L/kg, respectively. A terminal half time of 24 min could be calculated. Total clearance amounted to 112 mL/min/kg, while the area under the curve was 408 (microg/mL) min.

SINGLE INHALATION EXPOSURE

It is mentioned that fits were done for the two compartment model for each of the group/sex/dose combinations. However the resulting equations are not presented. The kinetic constants calculated from these fits are listed in a table. Most 50 ppm blood concentrations were below the level of detection. Only the plateau blood concentration for the 50 ppm males is available. Based on the 500 ppm and 800 ppm values the following constants were calculated for males and females respectively: half time uptake: 9, 8, 7, and 8 min; C180: 0.8, 11.2 and 19.3 microg/mL for males and 6.9 and 11.2 microg/L for females; area under the curve (AUC): 2033, 3110, 1181 and 2041 ppm min; AUC/dose: 4.1, 3.9, 2.4 and 2.6 (ppm min)/ppm.

REPEATED INHALATION EXPOSURE

The results for the blood concentrations are graphically presented in the publication. Relatively constant concentrations were found over the 13 -week period (measured at 2, 4, 8 and 13 weeks) for all three male groups. The female 800 ppm and 500 ppm showed a decrease over time. The 500 ppm concentrations were roughly between 10 and 13 µg/g for both sexes; the 800 ppm values were roughly between 15 and 23 µg/g (estimated from graphical presentation).

Results of urine TTCA concentrations were only presented for the repeated inhalation exposure. Again a graphical presentation is used. The following are rough estimates from these figures. The timedependence of the concentrations was not clear; may an initial increase is occurring. All 50 ppm levels are well below 100 µg total TTCA; the 500 ppm values range roughly from 200 to 340 µg for the males and from 150 to 270 µg for the females, these ranges are 330 to 360 µg and 150 and 170 µg for 800 ppm. The differences between the 500 ppm and 800 ppm are small and generally not statistically significant.

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
The study gives elementary insight into the kinetics of absorption, distribution and elimination of CS2 in rats upon inhalation. Moreover it gives information about the excretion of the "biomonitoring metabolite TTCA" in the urine. Uptake in the blood is rapid and a blood equilibrium was reached in about 90 min, although a slight increase continued thereafter. Elimination was also rapid and biphasic (rapid and more slow phase). Terminal elimination times varied from 41 to 77 min. The areas under the curves point to a saturation of elimination at the higher air concentrations. It appears that at high exposure levels TTCA does not correlate well with exposure.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Executive summary:

What follows is the abstract of the publication as published on PubMed (http://www.ncbi.nlm.nih.gov/pubmed)

Carbon disulfide (CS2) is an important industrial chemical widely used in the production of rayon, cellophane, fungicides and biocides. The uptake and elimination kinetics of CS2 was characterized for a single i.v. dose and for a single inhalation exposure. The uptake of CS2 into the blood was rapid with half times of 6 to 9 minutes. Elimination was relatively quick with terminal elimination half times of 41 to 77 minutes. The plateau CS2 blood concentration was lower in females than in males and lower in the male 50 ppm treatment group than would be predicted by linear dose proportionality compared to the 500 ppm and 800 ppm treatments. The CS2 blood concentration for the female 50 ppm group was below the limit of detection. The total and central compartment apparent volumes of distribution, 4.2 l/kg and .9 l/kg, were estimated from a single 50 mg/kg i.v. dose. The concentration of CS2 in blood resulting from repeated exposure, was investigated in a 13 week inhalation study. Blood samples were taken in rats previously exposed to 0, 50, 500, and 800 ppm CS2 for 2, 4, 8, or 13 weeks. The concentration of CS2 in the blood of male rats remained relatively constant throughout study. However the female 500 and 800 ppm groups showed a marked decrease over the course of the 13 week study. The concentration of CS2 in the blood from the 500 and 800 ppm groups of both sexes at all time points was higher compared to the 50 ppm group, than would be predicted by linear dose proportionality. The concentration of 2-thiothiazolidine-4-carboxylic acid in urine collected from the same animals lacked dose proportionality between the treatment groups at all time points. CS2 exposure caused dose-related decreases in body weight gain in both male and female rats.

In the same study, the distribution and elimination kinetics from blood were determined following single intravenous administration of CS2 (50 mg/kg)into the tail vein. Both parameters were modeled using a two compartment model with first order elimination from the central compartment. The apparent total volume of distribution was 4.2 L/kg, the terminal elimination half-life was 24 min, and the total clearance was 112 mL/min/kg.

Finally, in this study, experiments were conducted with rats exposed via inhalation to 50, 500, and 800 ppm, respectively, for up to 13 weeks. In males, blood concentrations of CS2 remained relatively constant throughout but decreased in females with increasing duration of the study. Nonlinear kinetics were observed: At all time points, the CS2 concentration in blood of the 500- and 800 -ppm males and females were significantly (about 1.5-2 times) higher compared with the 50-ppm group than would be expected by linear dose proportionality. Nonlinear kinetics was also observed in the excretion of the metabolite thiazolidine-2-thione-4 -carboxylic acid (TTCA) in urine of repeatedly exposed rats.The total excretion of TTCA during 18 h was not different between animals exposed to CS2 at 500 and 800 ppm (except for males after 2 weeks). The excretion of TTCA in the 50-ppm group was lower than that in the two other groups exposed to CS2, but the difference was less than would be predicted by dose proportionality. Taken together, these results indicate that uptake may be more efficient at higher concentrations or, more likely, metabolism and elimination pathways become saturated at the higher concentrations.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

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:

Objective of study:

distribution

Qualifier:

no guideline followed

Principles of method if other than guideline:

Pregnant mice were exposed to 35S-labelled CS2 or 14C-labelled CS2 via inhalation and the distribution of the label over the body was ivestigated by means of autoradiography.

GLP compliance:

not specified

Remarks:

It is not applicable for publications in peer-reviewed scientific journals

Radiolabelling:

yes

Remarks:

35S- or 14C-labelled CS2

Species:

mouse

Strain:

C57BL

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 3 months old
- Diet: ad libitum
- Water: ad libitum

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

10 min

Remarks:

Doses / Concentrations:
750 ppm

No. of animals per sex per dose / concentration:

40 (20 animals to 35S-labelled CS2 and 20 animals to 14C-labelled CS2; only pregnant females were exposed.

Control animals:

not specified

Positive control reference chemical:

Not appliccable to this type of study.

Details on study design:

Whole body low temperature autoradiography was performed at day 14 and day 17 day of the gestation period (mid and late) .
Whole body conventional autoradiography (for non-volatile radioactivity) was performed at days 9, 14 and 17 of gestation (early, mid and late).
Autoradiography was performed immediately upon inhalation, and after 1, 4, and 24 hours.
The presence of firmly-bound radiolabel was studied by applyinf the conventional technique to freeze dried, evaporated and extracted sections.

Details on absorption:

See below under "Any other information on results incl. tables"

Details on distribution in tissues:

See below under "Any other information on results incl. tables"

Details on excretion:

Not applicable

Metabolites identified:

Details on metabolites:

Distribution of 14C- or 35S-labelled material over the pregnant female and the foetus was studied.

DISTRIBUTION OF 35S-LABELLED MATERIAL

DAY 9

Labelled material was immediately passed over to the embryo, with an even distribution over the embryo. A peak of radioactivity was reached after 1 hour. Then the embryonic radioactivity was much higher than that in the maternal serum. It reached several times higher levels in the embryonic neuroepithelium than in the maternal brain. Radioactivity was found to be much less after 4 hours and insignificant at 24 hours. As no low-temperature autoradiography could be performed, no information is obtained about the volatile radiolabel

DAY 14

Volatile radiolabel (observed by means of low-temp. autoradiogr.) was specifically found in the ventricular cerebrospinal fluid up to 1 hours after exposure. Volatile radiolabel reached equal levels in placenta, foetal tissues and maternal blood. Maternal organs with a high metabolic or excretory activity showed higher radiolabel than those organs in the foetuses.

Conventional autoradiography yielded results comparable to those of gestation day 9, but for a concentration of radiolabel in brain, eyes, and skeleton, while at the longer post-exposure times the foetal cartilage was clearly labeled (non-extracabele material) in the absence of clear labelling of other tissues.

DAY 17

Immediately upon exposure high levels of volatile radiolabel (low temp autoradiography) were observed in placenta, umbelical cord, foetal blood, liver and eyes. At the same time, relatively low labelling was seen in maternal and foetal brain.

At later post-exposure times, both techniques revealed relatively strong non-extractable labeling of the foetal cartilage. Relatively low radiolabel was detected in the foetal brain, in contrast to the earlier gestation days.

DISTRIBUTION OF 14C-LABELLED MATERIAL

The results were comparable with those for 35S when the conventional technique was applied (non-volatile radiolabel), but for the fact that in case of 14C there was still radiolabel observed at 24 hours.

Application of the low-temp technique, als gave comparable results.

Freeze dried and evaporated sections showed relatively strong labelling (even 24 hours post exposure) in the foetal liver at day 14 and day 17 and in the foetal brain at day 14, while this organ had remarkably low levels at day 17. At day 17, the foetal urinary tract contained high levels of 14C radiolabel. Low levels of 14C radiolabel were seen in the foetal bone.

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
The study demonstrates the distribution of 35S- and 14C-labelled CS2 and metabolites over pregant mice at early, mid and late gestation. Application of low-temperature autoradiography and includng freeze dried, evaporated and extracted sections allowed for discerning volatile, non-volatile and tightly-bound radiolabel. High levels of metabolites of CS2 were registered in the embryonic neuroepithelium. In mid and late gestation CS2 itself accumulated in the cerebrospinal fluid (CSF) of the brain. 14C-labelled metabolites of CS2 showed affinity for bone and were retained in the liver even at long survival times (24 hours). These localizations may be of significance for some of the reported teratogenic effects of CS2, such as hydrocephalus, ossification defects and foetal liver injury, and support the idea that CS2 and/or its metabolites are embryotoxic and teratogenic by acting directly on embryonal and foetal structures.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Executive summary:

What follows is the abstract of the pubication as it is published on PubMed (http://www.ncbi.nlm.nih.gov/pubmed/)

Occupational exposure to carbon disulfide (CS2) has been associated with an increased rate of spontaneous abortions. Animal experiments have shown that CS2 is embryotoxic and teratogenic. In the present study, the embryonal and foetal distribution of CS2 and its metabolites was studied after administration of 35S- or 14C-labelled CS2 to pregnant mice in different stages of gestation. CS2 and its metabolites passed the placenta at all stages of gestation. High levels of metabolites of CS2 were registered in the embryonic neuroepithelium. In mid and late gestation CS2 itself accumulated in the cerebrospinal fluid (CSF) of the brain. 14C-labelled metabolites of CS2 showed affinity for bone and were retained in the liver even at long survival times (24 hours). These localizations may be of significance for some of the reported teratogenic effects of CS2, such as hydrocephalus, ossification defects and foetal liver injury, and support the idea that CS2 and/or its metabolites are embryotoxic and teratogenic by acting directly on embryonal and foetal structures.

Reference 3

Endpoint:: basic toxicokinetics
Type of information:: other: published data
Adequacy of study:: supporting 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:: Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Objective of study:: absorption; distribution; excretion; metabolism
Qualifier:: no guideline followed
Principles of method if other than guideline:: An extensive review of the literature up to the beginning of the 1990s. This covers a wide array of methods to study the toxicokinetics.
GLP compliance:: not specified
Remarks:: Not applicable to series of reviewed studies.
Radiolabelling:: other: Several studies made use of radiolabeled material; the C or the S atom of the molecule were replaced by radioactive isotopes (14C or 35S).
Species:: other: Various species were used, depending on the study reviewed.
Strain:: other: Various species were used, depending on the study reviewed.
Route of administration:: other: Invasive (injection) and non-invasive (inhalation, oral, dermal) techniques were used, depending on the purpose of the reviewed studies.
Vehicle:: other: Invasive (injection) and non-invasive (inhalation, oral, dermal) techniques were used, depending on the purpose of the reviewed studies.
Duration and frequency of treatment / exposure:: Not applicable: review paper.
Remarks:: Doses / Concentrations:
Not applicable: review paper.
No. of animals per sex per dose / concentration:: Not applicable: review paper.
Control animals:: not specified
Details on study design:: Not applicable: review paper.
Details on dosing and sampling:: Not applicable: review paper.
Statistics:: Not applicable: review paper.
Preliminary studies:: Not applicable: review paper.
Details on absorption:: See below under "Any other information on results incl. tables"
Details on distribution in tissues:: See below under "Any other information on results incl. tables"
Details on excretion:: See below under "Any other information on results incl. tables"
Metabolites identified:: yes
Details on metabolites:: The compound is well absorbed after inhalation, oral exposure and dermal exposure. Due to its lipophilicity it has a tendency to be transported to organs as the liver and the brains. Several metabolic pathways exist in mammals. Mixed function oxisases can oxidize the compound. This is followed by mineralization (CO2, sulfur, SO4), or the formation of monothiocarbamates via carbonyl sulfide (S=C=O). The first step can also entail the reaction with the amino groups of aminoacids. This results ultimately in the formation of dithiocarbamates. Then there is the direct conjugation of CS2 with glutathione, which gives rise to thiazolidine thione carboxylic acid (TTCA). TTCA is in urine is a used as a measure for exposure of humans. Carbonyl sulfide can also conjugate with glutathione, resulting in the formation of oxo-TTCA. Moreover, carbonyl sulfide can be metabolized to thiourea. The relative importance of these pathways in humans is not fully clear. However, it seems that no mineralization occurs in humans. Dithiocarbamates are regarded as an acid labile "store" of bound CS2. Unmetabolized CS2 is largely excreted by exhalation; a tiny part of the dose appears to leave the body via the urine. The metabolites leave the body via the urine, with the exception of CO2.
Conclusions:: Interpretation of results : no bioaccumulation potential based on study results
An extensive review of the toxicokinetics is presented. There is sample information avaible on this aspect of the toxicology of CS2. It can be consisely summarized as follows. The compound is well absorbed after inhalation, oral exposure and dermal exposure. Due to its lipophilicity it has a tendency to be transported to organs as the liver and the brains. Several metabolic pathways exist in mammals. Mixed function oxisases can oxidize the compound. This is followed by mineralization (CO2, sulfur, SO4), or the formation of monothiocarbamates via carbonyl sulfide (S=C=O). The first step can also entail the reaction with the amino groups of aminoacids. This results ultimately in the formation of dithiocarbamates. Then there is the direct conjugation of CS2 with glutathione, which gives rise to thiazolidine thione carboxylic acid (TTCA). TTCA is in urine is a used as a measure for exposure of humans. Carbonyl sulfide can also conjugate with glutathione, resulting in the formation of oxo-TTCA. Moreover, carbonyl sulfide can be metabolized to thiourea. The relative importance of these pathways in humans is not fully clear. However, it seems that no mineralization occurs in humans. Dithiocarbamates are regarded as an acid labile "store" of bound CS2. Unmetabolized CS2 is largely excreted by exhalation; a tiny part of the dose appears to leave the body via the urine. The metabolites leave the body via the urine, with the exception of CO2.

Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
Executive summary:: An extensive review of the toxicokinetics is presented. There is sample information avaible on this aspect of the toxicology of CS2. It can be consisely summarized as follows. The compound is well absorbed after inhalation, oral exposure and dermal exposure. Due to its lipophilicity it has a tendency to be transported to organs as the liver and the brains. Several metabolic pathways exist in mammals. Mixed function oxisases can oxidize the compound. This is followed by mineralization (CO2, sulfur, SO4), or the formation of monothiocarbamates via carbonyl sulfide (S=C=O). The first step can also entail the reaction with the amino groups of aminoacids. This results ultimately in the formation of dithiocarbamates. Then there is the direct conjugation of CS2 with glutathione, which gives rise to thiazolidine thione carboxylic acid (TTCA). TTCA is in urine is a used as a measure for exposure of humans. Carbonyl sulfide can also conjugate with glutathione, resulting in the formation of oxo-TTCA. Moreover, carbonyl sulfide can be metabolized to thiourea. The relative importance of these pathways in humans is not fully clear. However, it seems that no mineralization occurs in humans. Dithiocarbamates are regarded as an acid labile "store" of bound CS2. Unmetabolized CS2 is largely excreted by exhalation; a tiny part of the dose appears to leave the body via the urine. The metabolites leave the body via the urine, with the exception of CO2.

Reference 4

Endpoint:

basic toxicokinetics

Type of information:

other: published data

Adequacy of study:

supporting 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:

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Review of a large series of publications on studies in which a wide array of methods was applied.

GLP compliance:

not specified

Remarks:

Not applicable to review paper; it is not customary to refer to GLP in published peer-reviewed scientific paper.

Radiolabelling:

other: In some of the reviewed studies 14C- or 35S-labelled CS2 was used.

Species:

other: A series of studies with various animal species or humans was reviewed.

Strain:

other: A series of studies with various animal species or humans was reviewed.

Details on test animals or test system and environmental conditions:

Such details are often not provided in reviews.

Route of administration:

other: Invasive (injection) and non-invasive (inhalation, oral, dermal) routes were employed in the different studies reviewed.

Vehicle:

other: Invasive (injection) and non-invasive (inhalation, oral, dermal) routes were employed in the different studies reviewed.

Duration and frequency of treatment / exposure:

Not applicable: review paper.

Remarks:

Doses / Concentrations:
Not applicable: review paper.

No. of animals per sex per dose / concentration:

Not applicable: review paper.

Control animals:

not specified

Details on study design:

Not applicable: review paper.

Details on dosing and sampling:

Not applicable: review paper.

Statistics:

Not applicable: review paper.

Preliminary studies:

Not applicable: review paper.

Details on absorption:

See below under "Any other information on results incl. tables"

Details on distribution in tissues:

See below under "Any other information on results incl. tables"

Details on excretion:

See below under "Any other information on results incl. tables"

Metabolites identified:

yes

Details on metabolites:

See below under "Any other information on results incl. tables

What follows is the section in the review on the toxicokinetics of CS2. The reader is referred to the original report for the references.

5.1 Absorption

5.1.1 Human studies

Absorption by inhalation

Inhalation is the main route of carbon disulphide intake during occupational exposure. Investigations among volunteers and occupational exposed workers resulted in widely differing data on retention and on the time needed to attain equilibrium between the inhaled and the exhaled concentration. This is demonstrated by results of recent studies: Rosier et al (1987a) did not find an equilibrium after four consecutive exposure periods of 50 min each, whereas Herrmann et al (1982) postulated, based on 30 min experiments, that equilibrium is reached after approximately 45 min. Generally, equilibrium is attained during the first two hours of exposure. Retention declined from an initial 70%-80% of the inhaled CS2 to 15%-45% at equilibrium.

Retention is influenced by several factors. A difference between the retention in not previously exposed volunteers and that in chronically occupational exposed workers was noted. Furthermore, physical workload caused a decrease in retention and at the same time an increase in the respiratory volume (Herrmann et a11983; Rosier et al 1987a). As the respiratory volume is the most important factor, increasing workload results in increasing CS2 uptake (Herrmann et al, 1983). Finally, Rosier et al (1987a) observed a positive correlation between the percentage of fatty tissue and the retention of CS2.

Percutaneous absorption

Percutaneous absorption is the second potential source of occupational exposure to CS2. Skin absorption was evaluated by Baranowska and Dutkiewicz (1965) from experiments in which the hands were immersed in aqueous CS2 solutions. The amount of CS2 absorbed through the skin was determined by measuring the loss of CS2 from the solution. Loss of CS2 due to volatilisation was prevented by using polyvinyl foil sleeves and determined to be zero for at least 1 h. Using solutions with CS2 concentrations varying from 0.42 to 1.49 g/liter resulted in mass lossen from 74 to 268.5 mg. The calculated absorption velocity ranged from 0.23 to 0.79 mg.cm-2.h-1 (This figure may overestimate the actual uptake of CS2 into the blood, because subdermal fats may retain the substance to a large, but unknown extent).

5. 1.2 Animal studies

Absorption by inhalation

Studies in rabbits indicated retention values of 70%-80% when equilibrium was reached, 1.5-2.5 h after the beginning of exposure (Fielder and Shillaker 1981).

Percutaneous absorption

There is limited information available on skin absorption in animals. Exposure of rabbit skin to concentrations of 2500 mg/m3 (800 ppm) and higher for 1 h resulted in detectable amounts of in the breath of animals. No CS2 was detected in the breath of rabbits exposed to concentrations of 470 mg/m3 (150 ppm) for 6 h (Fielder and Shillaker 1981).

5.2 Distribution

After absorption, CS2 is distributed by the blood to the organs. CS2 can exist in blood as free CS2 and as acid-labile CS2 (ALCS2); the latter fraction can be recovered by acid treatment at elevated temperatures.

In rats, after exposure to CS2, the majority of the compound (about 90%) was found in the red blood cells. These cells are thought to play an important role in the transport of CS2 from the lung to the tissues and vice versa (Lam et al 1986). The majority of ALCS2 (about 90%) was also present in the red blood cells. ALCS2 was mainly bound to haemoglobin and, to a small extent, to other blood proteins (Lam and DiStefano 1986).

Lam and DiStefano (1982, 1983) showed that levels of free CS2 and of ALcS2 in blood are linearly related to the concentration in air inhaled by rats exposed to 15-120 mg/m3 (4.8-38.4 ppm) (for 8 h or 500-4000 mg/m3 (160-1280 ppm) for 4 h. ALCS2 in blood also increased linearly with time, when rats were exposed to 2000 mg/m3 (640 ppm) 0 ofcS2 for up to 4 h (Lam and DiStefano 1982). Under these conditions concentrations of free CS2 in red blood cells approached a plateau within 2 h, and in plasma within 15 min of exposure (Lam et al 1986).

CS2 is readily distributed to the tissues and organs. Rosier and Van Peteghem (1987) have determined tissue/air partition coefficients for CS2 from pig tissue ho¬mogenates to human blood. These coefficients varied from 2.4 for muscle to 4.4 for brain, while the coefficient for fatty tissue was 54.3.

Bergman et al (1984) studied distribution patterns in male mice after inhalation of 2340 mg/m3 (750 ppm) of 35S-labelled or 14C-Iabelled CS2 during 10 min by the use of low-temperature whole-body radiography. The distribution was followed up to 48 h. In contrast to other authors, they reported higher binding of C- than of S-metabolites, which was explained by differences in species, routes of administration and observa¬tion time. Immediately after inhalation a very high uptake of C35S2 or 14CS2 was found in body fat, nasal mucosa, blood, and well-perfused organs as liver, kidney, and lung; very little was found in the brain and the endocrine tissue. 35S-metabolites were ini¬tially concentrated in the liver and the kidney, but were rapidly eliminated from the body. There was evidence of an extensive metabolic incorporation of sulphur originating from CS2 during its biotransformation. 14C-metabolites were likewise concentrated in liver and kidney, but also in nasal mucosa, bronchi, bone, pancreas, thyroid, adrenal cortex, and testes. These metabolites were retained in large amounts in liver, thyroid (follicles), nasal mucosa, bronchi, and kidney.

Green Snyderwine and Hunter (1987) examined the distribution of 14CS2 and C35S2 in 1- to 40-day-old rats by i.p. administration. Three hours after administration the tissue level of 35S-CS2-derived radioactivity exceeded levels of 14C-CS2-derived radioactivity indicating that sulphur metabolites free from the carbon atom of CS2 were formed in rats as young as 1 day of age. 35S covalently bound to tissue protein was significantly higher in 1- through 20-day-old rats than in 30- and 40-day-old rats. 24 h after dosing, up to 13 times more 35S-labelled metabolites were covalently bound in organs from 1-day-old rats than in similar organs from 40-day-old rats.

Finally, Danielsson et al (1984) carried out inhalation studies by exposing preg¬nant mice to 2340 mg/m3 (750 ppm) of 14CS and C35S2. They examined the embryonal and foetal distribution of CS2 and its metabolites in different stages of gestation. CS2 and its metabolites passed the placenta at all stages of gestation. High levels of CS2 metabolites were noted in the embryonic neuroepithelium. In mid and late gestation CS2 accumulated in the cerebrospinal fluid. 14c metabolites showed affinity for bone and were retained in the liver even at long survival time (24 h).

There is only one report containing data on distribution of CS2 in humans. Milk from nursing mothers occupationally exposed to 29-66 mg/m3 (9.3-21.2 ppm) for 6.5 h contained an average of 0.12 mg of CS2. Exposure to 23-125 mg/m3 (7.4-40 ppm) for 2-4 h resulted in a lower average milk concentration of 0.07 mg/liter. These data suggest, that the CS2 content in mother milk is related to the product of the CS2 exposure level and the exposure time. CS2 was still present in preshift samples. CS2 was also detected in the urine of 5 out of 10 nursed babies and in the umbilical blood of one newborn, indicating that CS2 can reach the foetus through the placenta (Cai and Bao 1981).

5.3 Biotransformation

CS2 reacts easily with amino groups of proteins and other substances resulting in the formation of dithiocarbamates and thiazolinone. Furthermore, CS2 can react with glutathione and cysteine to 2-thiothiazolidine-4-carboxylic acid (TTCA). Less than 6% of the absorbed CS2 is metabolized to TTCA (Campbell et a11985; Rosier et al 1987b).

Finally, desulphuration of CS2 takes place in the liver. The initial step in the process is catalysed by the cytochrome P450 containing mono-oxygenase system, in which two forms of cytochrome P450 are involved (Rubin and Kroll 1986; Torres et al 1981). The products of this reaction are monothiocarbamate (the hydrate form of COS) and a reactive sulphur species, which either binds to microsomal macromolecules or is oxidised to sulphate. The monothiocarbamate can either be converted to COS in an equi¬librium reaction catalysed by carbonic anhydrase or to carbon dioxyde and the hydrogen sulphide ion, which is oxidised to thiosulphate and sulphate (Chengelis and Neal 1987).

5.4 Elimination

In rats exposed to 500-4000 mg/m3 (160-1280 ppm) for 4 h free CS2 was rapidly eliminated from the blood by a two-exponential first order process with half-lives of 8.7 and 55.2 min. ALCS2 was similarly, but more slowly, eliminated with half-lives of 2.2 and 42.7 h (Lam and DiStefano 1982). ALCS2 was also slowly eliminated from tissue. The expected accumulation of ALCS2 in the blood was confirmed by an experiment in which rats were daily exposed to 120 mg/m3 (38 ppm), 8 h per day for 6 days. By the end of the exposure period the level of blood ALCS2 was about 2.5 times that after the first 8 h exposure and about 3 times the level of free CS2. In man, about 10%-30% of the amount of CS2 absorbed after inhalation is excreted unchanged in the breath. The first phase of elimination is fast: the half-life is about 10 min. Since CS2 was detected in breath 16 h after exposure, there is evidence for at least two pharmacokinetic compartments (Campbell et al 1985). This was confirmed by Rosier et al (1987a). They characterised the course of the respiratory elimination of CS2 during a post-exposure period of 180 min by an initially fast decrease with a half-life of about 1 min followed by a relatively slow decrease with a half-life of about 110 min. Baranowska and Dutkiewicz (1965) found a much lesser degree of excretion of unchanged CS2 in exhaled breath after absorption through the skin: 6% (range: 2%-11 %).

Less than 1% is excreted unchanged in the urine. The remainder 70%-90% is metabolized. The metabolites are excreted in the urine and in the breath (as CO2). No data on half-life as to excretion in the urine were found.

The fact that 35S was found in the intestines of rats after exposure to C35S2 may indicate that some metabolites are excreted in the faeces (Bergman et al 1984).

5.5 Biological monitoring

5.5.1 Determination of CS2

In breath

CS2 is excreted unchanged in breath. This process can be described by means of a two-exponential decay, with half-lives for the first phase of 1 and 10 min (Campbell et al 1985; Rosier et aI1987a). For the second phase a half-life of 110 min has been reported (Rosier et al 1987a).

Two reports are dealing with the possibility of measuring CS2 in expired air as a biological monitoring method. Campbell et al (1985) used a transportable mass spectrometer which could measure concentrations below 1 ppm with a fast response enabling the real-time analysis of the solvent without the use of breath collection devices. CS2 could be measured in end-of-shift as well as in preshift samples. The CS2 levels in the end-of-shift samples varied widely, probably due to fluctuating exposure levels toward the end of shift and may only reflect exposure in the period just before sampling. The significance of next-day preshift samples when the rates of elimination are much slower, was not evaluated. Rosier et al (1987a) also found a considerable dispersion of the individual respiratory elimination of carbon disulphide. They concluded that it was not possible to employ the total amount of CS2 eliminated during 3 h postexposure to estimate the respiratory uptake during exposure. In addition, as the concentration of CS2 in exhaled air at the end of exposure falls rapidly, the moment of sampling became too critical, so this method was considered to be useless in evaluating recent exposure.

In blood

The determination of CS2 in the blood did not give reproducible results and the correlation between CS2 concentrations in blood and air was very weak or non-existing. This was explained by the observation of the existence of two forms of CS2 in the blood: free and ALCS2. Free CS2 disappears very quickly. Campbell et al (1985) were not able to detect free CS2 in blood samples from exposed workers using head-space gas chromotography.

In urine

Only 1 % or less of the absorbed amount of CS2 is excreted unmetabolised in the urine. The determination of CS2 in urine was therefore deemed unsuitable as an exposure test (WHO 1979). However, Leuschke et al (1980) found a significant relationship be¬tween exposure and excretion of CS2 in urine. After correction for the density of the urine and for the concentration of CS2 in the urine at the beginning of the shift, this re¬lation could be described by:

U = 0.00242 c t - 0.02 (n=6, s_yx=0.82)

in which U is the CS2 concentration in urine in µmol/liter, c the CS2 concentration in air in mg/m3 and t the exposure time. This equation resulted from studying a limited number of exposed persons (n=6) and was not further validated, so its actual value remains questionable.

5.5.2 Determination of metabolites

The majority of CS2 in the blood is in bound form and can be released using acid and heat. This product, ALCS2, was slowly eliminated and blood concentrations appeared to be linearly related to the inhalation concentration and time, as was shown in experiments with rats. Rats exposed to 67 mg/m3 (21 ppm) of CS2 for 8 h had measurable concentrations of blood ALcS2 using a colorimetric method (Lam and DiStefano 1982). Campbell et al (1985) used a headspace gas chromatographic technique to detect ALCS2 in the blood of exposed workers. Although the technique was very selective and sensitive, some difficulties remained in terms of reproducibility and the correlation between ALCS2 and exposure was not very satisfactory.

In urine

One of the metabolites of CS2 excreted in the urine has been identified as 2-thiothiazolidine-4-carboxylic acid (TTCA). This metabolite was specific for CS2 exposure and not found in the urine of workers exposed to other solvents (Van Doorn et al. 1981). Rosier et al (1984) found a good relation between the TTCA levels in end-of-shift urine and exposure (exposure levels: 15-160 mg/m3 or 5-51 ppm), especially when urine samples with creatinine concentrations below 1 mg/cm3 were disregarded (r=0.86; n=13). Campbell et al (1985) confirmed these findings (r=0.84) in a group exposed to 5-24 mg/m3 (2-8 ppm), measured by personal air sampling with pumps. They calculated a concentration of TTCA of 4 mmol per mol creatinine to be equivalent to an exposure of30 mg/m3 (10 ppm; 8-h TWA). Meuling et al (1989) found even a better correlation coefficient of 0.92 in workers exposed to an average level of 13 mg/m3 (4 ppm; range: 1-66 mg/m3 or 0.3-21 ppm; n=28), measured using diffusion badges. Based on group observations, the relative TTcA concentration that precludes 95% confidence exposures exceeding 60 mg/m3 (20 ppm; the current Dutch MAC-value) is 0.94 mmol per mol creatinine (1.27 mg/g creatinine) in urine sampled during the last 4 h of a shift.

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
An extensive review of the toxicokinetics is presented. There is ample information avaiable on this aspect of the toxicology of CS2. The major conclusions are presented in the Executive Summary below.
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Executive summary:

What follows is the summary of the toxicokinetics section in the original review report.

Although CS2 may be absorbed through the skin, the main route of occupational exposure is inhalation. Equilibrium is reached within the first two hours of exposure, when lung retention declines from an initial 70%-80% to 15%-45%. The retention is usually lower in those exposed for the first time. Furthermore, increased workload results in decreased retention and an increase in respiratory volume with as overall effect an increased CS2 uptake. The red blood cells play an important role in the distribution of CS2 to the organs and tissues: the two forms of CS2 found in the blood of animals, i.e. free CS2 and ALCS2 (a bound fraction that can be recovered by acid treatment at elevated temperatures), were mainly bound to the erythrocytes. Free CS2 disappeared rapidly from the blood, whereas ALCS2 was eliminated much more slowly and was shown to accumulate. CS2 and its metabolites were found in many organs and tissues of experimental animals although preference was observed towards body fat, liver, and kidney. Studies in pregnant mice show CS2 and its metabolites to pass the placenta at all stages of gestation. As to man, CS2 was detected in the breast milk of exposed Chinese workers and in the umbilical blood of one newborn baby.

10-30% ofthe absorbed CS2 is exhaled unchanged by an initial fast (half-life 1-10 min) and a second slower phase (half-life 110 min). Only a minor quantity (less than 1 %) is excreted unchanged in the urine. The remaining 70%-90% is metabolized. Desulphuration occurs in the liver by the MFO system, resulting in a variety of products (CO2, COS, thiosulphate, sulphate and a reactive sulphur species). Furthermore, CS2 easily reacts with amino groups of amino acids and other substances to dithiocarbamates and thiazolinone, and with glutathione and cysteine to TTCA. TTCA is a specific metabolite of CS2 and measurement of its concentration in the urine offers a method for biological monitoring of exposed workers.

Reference 5

Endpoint:

basic toxicokinetics

Type of information:

other: published data

Adequacy of study:

supporting 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:

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Review paper based on many studies in which a wide array of methods and techniques were applied.

GLP compliance:

not specified

Remarks:

Not applicable to reviews; it is not customary to refer to GLP in studies published in peer-reviewed scientific papers.

Radiolabelling:

other: In some of the reviewed studies 14C- or 35S- labelled substance was applied.

Species:

other: Different animal species as well as humans.

Strain:

other: Different animal species as well as humans.

Details on test animals or test system and environmental conditions:

Such details are often not provided in reviews.

Route of administration:

other: Various routes, invasive as well as non-invasive were applied.

Vehicle:

other: Various routes, invasive as well as non-invasive were applied.

Duration and frequency of treatment / exposure:

Such details are often not provided in reviews.

Remarks:

Doses / Concentrations:
Such details are often not provided in reviews.

No. of animals per sex per dose / concentration:

Such details are often not provided in reviews.

Control animals:

not specified

Details on study design:

Not applicable: review paper.

Details on dosing and sampling:

Not applicable: review paper.

Statistics:

Not applicable: review paper.

Preliminary studies:

Not applicable: review paper.

Details on absorption:

See below under "Any other information on results incl. tables"

Details on distribution in tissues:

See below under "Any other information on results incl. tables"

Details on excretion:

See below under "Any other information on results incl. tables"

Metabolites identified:

yes

Details on metabolites:

See below under "Any other information on results incl. tables". Metabolites identified are dithiocarbamates, trithiocarbamates TTCA (thiazolidine thione carb. acid), sulphur, sulphate, CO2.

What follows is a copy of the section on toxicokinetics in the review paper. The figure in the section is attached. The reader is referred to the original publication for the references.

4.1. Metabolism and Disposition

4.1.1. Human data

As shown in controlled exposure studies, CS2 is rapidly and extensively absorbed through the respiratory tract. Unmetabolized CS2 is mainly excreted via the lungs. Uptake through the skin was demonstrated from aqueous solutions ofCS2·

In a pharmacokinetic study (Teisinger and Soucek 1949), nine persons were exposed to analytically monitored concentrations of CS2 at 17-30 ppm (in one case to 51 ppm) for 1-4 h. In the first 15 min of exposure, about 80% of inhaled CS2 was retained. After 45 min and until the end of exposure, uptake decreased to about 40%. The percentage absorbed did not depend on the concen¬tration in the inhaled air. The blood:air coefficient of CS2 after 90-120 min was 2.2 on average. At the end of exposure, the concentration of CS2 in blood fell rapidly to 25% of the value present at the end of exposure within 1 h, and CS2 disappeared from blood after 2 h. Only a small portion (about 5%) of CS2 was eliminated by the lungs, and this elimination was largely completed 2 h after termination of exposure. Only minor amounts of unchanged CS2 could be detected in urine.

In a further study, volunteers inhaled CS2 at 38-52 ppm through face masks for 0.5-2 h (Harashima and Masuda 1962). During the first 10 min of exposure, on average, 51 % of the inhaled CS2 was exhaled in breath, and this percentage increased to 65% after 40 min when equilibrium was about reached. After exposure ceased, the concentration of CS2 in exhaled breath declined rapidly with a half-life in the order of 10 min. There was a high variation between individuals in the actual amount of absorbed CS2 that was exhaled after exposure (8-48%, average 23%). Less than 1% of unchanged CS2 was excreted through the skin.

Herrmann et al. (1982; 1983; 1985; 1989) conducted a series of toxicokinetic studies on inhalational uptake of CS2 in nonexposed and occupationally exposed workers. Up to12 test persons were exposed to analytically monitored concentrations of CS2 at 6-108 mg/m3 (l.9-35 ppm) via face mask. During the first 5 -min interval, individual retention ranged from 47% to 80%. After 30 min of exposure, individual retention values decreased to 38-71 % (n = 11; mean retention 48.7%). Regression analysis revealed that the retention increased significantly but slightly with increasing exposure concentration. Moderate exercise (100 W) decreased the retention after 30 min to 15-37%. In a further experiment with constant light exercise (25 W), the initial retention of about 50% dropped to about 33% after 30 min and was constant thereafter to the end of exposure (after 4 h). Demus (1964) obtained similar mean retention values of 5l.6% (range 43.5-60%, n = 11 individuals) after 30 min, 36.8% (26 -43.5%) after 2 hand 31.7% (20-40%) after 5 h at CS2 exposure concentrations of 53-445 µg/L (17 - 142 ppm).

Interindividual variation in the uptake of CS2 by inhalation proved significantly influenced by the amount of body fat. In a study (Rosier et al. 1987), six male human volunteers were exposed to CS2 at 10 and 20 ppm at rest and to 3 and 10 ppm under light physical exercise (50 W) for four consecutive periods of 50 min each. At rest, the retention values were about 40% at 10 ppm and 20 ppm. At physical exercise, the retention values decreased to about 28% at 3 ppm and 10 ppm. The most important fraction of the interindividual variation observed could be explained by the differences in percentage of body fat. During exposure, only an apparent steady state was reached. The exhaled concentration of CS2 followed over 180 min after exposure could be described by means of a biphasic elimination. There was an initial very fast decrease with a half-life of 1.1 min followed by a second slower decrease with a half-life of 109.7 min. The total amount of CS2 being exhaled in 180 min varied from 5.4 to 37.9%. Again, it could be shown that interindividual differences in body fat significantly determined this parameter.

Studies regarding the distribution of CS2 in humans were not available.

Limited data are available on the metabolism of CS2 in humans. In vitro studies have shown that CS2 combines with amino acids in human blood, and the so-called "acid-labile" CS2 (see section 4.l.2) is mainly (90%) found in the erythrocytes (Lam and DiStefano 1983; 1986).

Metabolites of CS2 are primarily excreted via the kidney. Several sulfur-containing urinary metabolites were identified including thiourea, 2 -thio-5 -thiazolidinone, and 2-thiothiazolidine-4-carboxylic acid (TTCA). These sub¬stances are formed by the reaction of CS2 with glutathione, cysteine, glycine, and other amino acids. Less than 5% of the CS2 taken up is excreted as TTCA. However, the excretion of TTCA is linearily correlated with the CS2 exposure occurring at today's workplaces. Therefore, this parameter is used in biologic monitoring (Drexler 1998). Recently, from the urine of workers exposed to CS2, 2-thioxothiazolidin-4-carbonylglycine (TTCG) was identified as a metabolite of CS2. This compound is suggested to be a precursor of TTCA (Amamath et al. 2001).

4.1.2. Animal Data

A number of studies have shown that CS2 is rapidly absorbed through the respiratory tract. Absorption of gaseous CS2 through the skin of rabbits was also demonstrated (Cohen et al. 1958).

The toxicokinetics of CS2 in rats was studied as part of the collaborative NIEHS study (Moorman et al. 1998) (see section 3.2.2). Male and female F344 rats were exposed nose-only to CS2 at 50, 500, and 800 ppm for 180 min, and blood samples were taken 4, 8, 15, 30, 60, and 180 min after the start of exposure. Values for kinetic parameters were calculated from the fits of a two compartment model to the blood concentration versus time. At 50 ppm, the blood concentration of CS2 was at the limit of quantification in males after 180 min (0.8 µg/mL) and below at all other time points and throughout in females. At 500 and 880 ppm, uptake in blood was found to be rapid with a half-time of 6-9 min. The concentration in blood at 180 min increased proportionally with dose and was significantly (about 40%) lower in females than in males. No true steady-state during the exposure was reached.

In the same study, the distribution and elimination kinetics from blood were determined following single intravenous administration of CS2 (50 mg/kg) into the tail vein. Both parameters were modeled using a two compartment model with first order elimination from the central compartment. The apparent total volume of distribution was 4.2 L/kg, the terminal elimination half-life was 24 min, and the total clearance was 112 mL/min/kg.

Finally, in this study, experiments were conducted with rats exposed via inhalation to 50, 500, and 800 ppm, respectively, for up to 13 weeks. In males, blood concentrations of CS2 remained relatively constant throughout but de¬creased in females with increasing duration of the study. Nonlinear kinetics was observed: At all time points, the CS2 concentration in blood of the 500 - and 800- ppm males and females were significantly (about l.5-2 times) higher compared with the 50-ppm group than would be expected by linear dose proportionality. Nonlinear kinetics was also observed in the excretion of the metabolite thiazolidine-2-thione-4-carboxylic acid (TTCA) in urine of repeatedly exposed rats. The total excretion of TTCA during 18 h was not different between animals exposed to CS2 at 500 and 800 ppm (except for males after 2 weeks). The excretion of TTCA in the 50 -ppm group was lower than that in the two other groups exposed to CS2, but the difference was less than would be predicted by dose proportionality. Taken together, these results indicate that uptake may be more efficient at higher concentrations or, more likely, metabolism and elimination pathways become saturated at the higher concentrations.

In a study with rabbits, blood equilibrium concentrations of CS2 were reached after exposure to 20-150 ppm for l.5-2 h. After exposure ended, 15 - 30% of the CS2 absorbed was excreted through the lungs and less than 0.1 % via the kidney. In rats exposed to CS2 at 60-350 ppm, the substance was rapidly eliminated during the first 6-8 h after exposure. Low concentrations of CS2 could still be detected in brain, liver, and kidney 20 h after exposure (Beauchamp et al. 1983).

Unmetabolized CS2 is largely excreted via the lungs, but most of the CS2 taken up is metabolized and eliminated in the form of various metabolites by the kidney.

The metabolism of CS2 involves the reaction with amino (NH2), sulfhydryl (SH), and hydroxyl (OH) groups on one hand and the reaction with the microsomal mixed-function oxidase cytochrome P-450 on the other (Figure 2-3). The reaction of CS2 with NH2 and SH and OH groups leads to the formation of the so-called "acid-labile" pool of bound CS2. This pool consists of dithiocarbamates, trithiocarbamates, and related sulfur containing products. Dithiocarbamates are the first reaction products of CS2 with the NH residues of amino acids, proteins, and catecholamines. Due to the reversible reaction, it is not possible to strictly distuinguish between "free" and "acid-labile" CS2 quantitatively (McKenna and DiStefano 1977a).

McKenna and DiStefano (1977a) studied the distribution of free and acidlabile CS2 in rats following inhalation of 2 mg/L (640 ppm). The concentration of free CS2 reached (liver, kidney, heart, muscle) or approached (brain) a steadystate level within 4 to 5 h of exposure in all tissues studied with the possible exception of fat. In contrast, the tissue level of acid-labile CS2 continued to increase until the end of exposure. The highest concentration of free CS2 was found in fat followed by adrenal glands and liver. Except for fat and blood, 40- 90% of the total CS2 in the tissues was found as acid-labile metabolites. In most tissues (adrenals, kidney, brain, muscle, heart), the concentration of acid-labile CS2 was higher than that of free CS2. The concentration of free CS2 declined rapidly after exposure ended, and the acid-labile CS2 was removed slowly. In brain, approximately one-third was detectable 16 h after exposure. In another study with rats exposed to CS2 at 640 ppm for up to 4 h, the half-life of elimination of free and acid-labile CS2 from blood could be described by a two-exponential, first-order process (Lam and DiStefano 1982). However, the halftimes greatly differed for free CS2 (about 9 and 55 min) and for acid-labile CS2 (2.2 and 42.7 h). When rats were repeatedly exposed over several days at 120 mg/m3 (40 ppm) for 8 h/d, acid-labile CS2 in blood continuously increased with each exposure, and free CS2 level remained relatively constant. By the sixth to seventh exposure, the acid-labile CS2 concentration was about 2.5 times that after the first exposure and about 3 times higher than the concentration of free CS2 (Lam and DiStefano 1983).

Studies with low-molecular-weight dithiocarbamates, such as diethylthiocarbamates, have shown that CS2 can be released in vivo. Therefore, the formation of thiocarbamates from CS2 and endogenous NH groups probably is at least partially reversible, and that amount of CS2 that is slowly eliminated with long half-life may be derived from this pool. On the other hand, subsequent reactions ofthiocarbamates may lead to long-lived protein modifications. Crosslinking of globin and spectrin in erythrocytes and of neurofilaments in spinal cord has been demonstrated in rats after repeated exposure to CS2 at 50 ppm by inhalation or repeated i.p. injection of 2 mmoLlkg (150 mg/kg) (Valentine et al. 1993, 1997, 1998; Erve et al. 1998a).

The cytochrome P-450 dependent oxidation of CS2 is probably catalyzed by the cytochrome P-450 isoenzyme that can be induced by ethanol. In the first step, an active sulfur atom and carbonyl sulfide (COS) are released. COS is further metabolized mainly by carboanhydrase to carbon dioxide and hydrogen sulfide (Chengelis and Neal 1980, 1987). Sulfur and sulfide are finally oxidized to sulfate entering the endogenous sulfate pool. The reactive sulfur also binds to macromolecules, including cytochrome P-450 monoxygenases. This reaction is held responsible for P-450 monoxygenase inhibition, which has been observed in many studies after exposure to CS2 in vivo and in vitro (e.g., Freundt et al. 1974b; Dalvi et al. 1975; Dalvi and Neal 1978), and for the hepatotoxicity of CS2 in phenobarbital pretreated rats (Chengelis 1988).

The extent to which CS2 is metabolized by the P-450 pathway is not clear.

The sulfur-containing metabolites, which are excreted in urine of humans (see section 4.1.1) and animals, derive from reaction products of CS2 with amino acids. In a study in rats exposed to CS2 at 50 or 500 ppm for 6 h, pretreatment with P-450 enzyme inducers (phenobarbital, ethanol, 3-methylcholanthrene) had no effect on the excretion of TTCA. On the other hand, administration of sub¬stances that deplete the level of tissue glutathione (phorone, diethyl maleate, buthionine sulfoximine) at least initially decreased the excretion of TTCA (Kivisto et al. 1995).

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.
A recent and thorough review of the literature on the toxicokinetics, which shows that there is ample knowledge about key aspects absorption, distribution, metabolism and excretion. It makes clear that CS2 is rapidly and extensively absorbed after inhalation. Depending on various factors (fat content, dose, exercise) between 20 to 50% is retained by humans. The unmetabolized CS2 is largely exhaled as id the CO2 formed, while other metabolites are excreted via the urine. CS2 is "stored" in the body is the form a dithiocarbamates. The free form is much more rapidly elimated than the "stored form". Metabolism occurs by mixed-function oxidase catalyzed oxidation or conjugation with SH- or NH- groups. The conjugations result in di- and trithiocarbamates and TTCA.

Executive summary:

In humans CS2 is rapidly and extensively absorbed through the respiratory tract. Within a few hours an equilibrium between inhaled and exhaled CS2 is established. Retention percentages varie, depending on air concentration, body fat and exercise. Percentages lie generally between 20% and 50% at equilibrium between inhalation and exhalation. Unmetabolized CS2 is mainly excreted via the lungs. After termination of exposure a biphasic elimination via exhalation was observed, with a half-life of 1.1 min and a half-life of 109.7 min Minor amounts are detected in the urine. Uptake through the skin was demonstrated from aqueous solutions of CS2. Studies regarding the distribution of CS2 in humans were not available.

Limited data are available on the metabolism of CS2 in humans. In vitro studies have shown that CS2 combines with amino acids in human blood, and the so-called "acid-labile" CS2 is mainly (90%) found in the erythrocytes. In humans, the metabolites of CS2 are primarily excreted via the kidney, among them thiourea, 2-thio-5-thiazolidinone, and 2-thiothiazolidine-4-carboxylic acid (TTCA), substances formed by the reaction of CS2 with glutathione, cysteine, glycine, and other amino acids.

Less than 5% of the CS2 taken up by humans is excreted as TTCA. However, the excretion of TTCA is linearily correlated with the CS2 exposure and this parameter is used in biologic monitoring.

In experimental animals CS2 is rapidly absorbed through the respiratory tract. In addition, absorption of gaseous CS2 through the skin of rabbits was demonstrated. Also in animals the unmetabolized CS2 is largely excreted via the lungs, but most of the CS2 taken up is metabolized and eliminated in the form of various metabolites by the kidney.

Distribution and elimination from blood in rats following a single intravenous administration of CS2 (50 mg/kg) was investigated. An apparent total volume of distribution was 4.2 L/kg was found and a terminal elimination half-life of 24 min and total clearance was 112 mL/min/kg. Semichronic exposure of rats by inhalation (50, 500 and 800 ppm) was found to go with a more efficient uptake at higher concentrations or a saturation of metabolism and elimination pathways at the higher concentrations.

In rabbits, blood equilibrium concentrations were reached after exposure to 20-150 ppm for l.5-2 h. After exposure ended, 15- 30% of the CS2 absorbed was excreted through the lungs and less than 0.1 % via the kidney. In rats exposed to CS2 at 60-350 ppm, the substance was rapidly eliminated during the first 6-8 h after exposure. Low concentrations of CS2 could still be detected in brain, liver, and kidney 20 h after exposure.

The metabolism of CS2 involves the reaction with amino (NH2), sulfhydryl (SH), and hydroxyl (OH) groups on one hand and the reaction with the microsomal mixed-function oxidase cytochrome P-450 on the other. The reaction of CS2 with NH2 and SH and OH groups leads to the formation of the so-called "acid-labile" pool of bound CS2. This pool consists of dithiocarbamates, trithiocarbamates, and related sulfur containing products. The acid-labile pool of CS2 and the free CS2 were found to demonstrate different kinetics upon inhalation in animals. Kinetics of the latter was more rapid than that of the former, while the maximum amount of free CS2 that is achieved after inhalation is lower that the amounts of acid-labile CS2 that can be reached. Both forms of CS2 show a biphasic elimination in rats; however for the free form half-life was 9 and 55 min and for acid-labile CS2 half-life of 2.2 and 42.7 h were found.

CS2 can be released in vivo from low-molecular-weight dithiocarbamates. Therefore, the formation of thiocarbamates from CS2 and endogenous NH groups probably is at least partially reversible. On the other hand, subsequent reactions of thiocarbamates may lead to long-lived protein modifications.

The cytochrome P-450 dependent oxidation of CS2 is probably catalyzed by the cytochrome P-450 isoenzyme that can be induced by ethanol. In the first step, an active sulfur atom and carbonyl sulfide (COS) are released. COS is further metabolized to carbon dioxide and hydrogen sulfide. Sulfur and sulfide are finally oxidized to sulfate entering the endogenous sulfate pool. The reactive sulfur also binds to macromolecules, which may lead to P-450 monoxygenase inhibition. The extent to which CS2 is metabolized by the P-450 pathway is not clear. The sulfur-containing metabolites, which are excreted in urine of humans and animals, derive from reaction products of CS2 with amino acids.

Reference 6

Endpoint:: basic toxicokinetics
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:: Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2
Objective of study:: metabolism
Qualifier:: according to guideline
Guideline:: EPA OPP 85-1 (Metabolism and Pharmacokinetics)
Qualifier:: equivalent or similar to guideline
Guideline:: EU Method B.36 (Toxicokinetics)
Deviations:: yes
Remarks:: Distribution was not investigated.
GLP compliance:: not specified
Radiolabelling:: yes
Remarks:: 14C-Ziram
Species:: rat
Strain:: Sprague-Dawley
Sex:: male/female
Details on test animals or test system and environmental conditions:: - Source: Charles River, US
- Age at study initiation: 44 days (m); 51 days (f)
- Weight at study initiation: 149-169 g (m); 145-162 g (f)
Route of administration:: oral: gavage
Vehicle:: CMC (carboxymethyl cellulose)
Duration and frequency of treatment / exposure:: Single and multiple (15 days daily) application
Remarks:: Doses / Concentrations:
Single: 15 and 352 mg/kg
Multiple: 15 mg/kg (14x nonradiolabeled; 1x radiolabeled)
No. of animals per sex per dose / concentration:: 5
Control animals:: yes, concurrent vehicle
Details on dosing and sampling:: - Tissues and body fluids sampled: air, urine, faeces, blood, several organs

The CO2 trapping solution and the volatile traps were collected at 0-4, 4-8, 8-12, and 12-24 h following administration of the radiolabeled Ziram and daily thereafter for a total of 4 days. Urine and faeces samples were collected at 0-6, 6-12, and 12-24 hours after the radiolabeled dose and daily thereafter for a total of 7 days. Urine and faeces were collected in plastic containers surrounded by ice. At the end of the collection period, the animals were anesthetized with halothane and exsanguinated by cardiac puncture. Blood (2 to 5 mL) was collected and weighed in heparinized tubes and saved for radioanalysis. After sacrifice the cages were washed with a 1.0% trisodium phosphate solution which was saved for analysis.
Details on absorption:: The mean 14C recovery ranged from 79% to 92% of the total doses administered.
Details on distribution in tissues:: The mean total radioactivity retained in the tissues and carcasses ranged from 1.11% to 1.92% of the total dose administered. For the low dose groups, the residue levels in the blood and tissues ranged from 0.05 to 2.5 ppm (µg 14C-Ziram equivalents/g sample). The highest levels were found in blood, liver, kidney, heart, lungs, spleen and thyroid gland.
Details on excretion:: The majority of the radioactivity was found in urine (17% to 35%), faeces (9% to 18%), and expired air (36% to 53%). The rate of elimination was relatively fast; the majority of the radioactivity was eliminated within 48 hours after dosing.
No apparent sex-related differences were observed for 14C elimination or distribution for any of the treated groups.
Metabolites identified:: yes
Conclusions:: Interpretation of results : no bioaccumulation potential based on study results
Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2
The mean total radioactivity retained in the tissues and carcasses ranged from 1.11% to 1.92% of the total dose administered. For the low dose groups, the residue levels in the blood and tissues ranged from 0.05 to 2.5 ppm (µg 14C-Ziram equivalents/g sample). The highest levels were found in blood, liver, kidney, heart, lungs, spleen and thyroid gland.

Reference 7

Endpoint:

basic toxicokinetics in vivo

Type of information:

other: published data

Adequacy of study:

weight of evidence

Study period:

1985

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:

Pentan-1-ol/Amyl alcohol is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, pentan-1-ol/Amyl alcohol need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Objective of study:

distribution

Qualifier:

no guideline available

Principles of method if other than guideline:

Analysis of tissue distribution of the test in rats substance after inhalation exposure

GLP compliance:

Radiolabelling:

Remarks:

alcohol and aldehyde concentrations were determined by gas chromatography

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 3 months
- Weight at study initiation: 254 ± 29 g for test group, 253 ± 22 g in control group

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

7-14 weeks, 5 days per week, 6 hours daily

Remarks:

Doses / Concentrations:
0.36, 1.08, 2.16 mg/l (100, 300, 600 ppm)

No. of animals per sex per dose / concentration:

Control animals:

yes, sham-exposed

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood, brain, liver, kidney
- Time and frequency of sampling: after 7 and 14 hours

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: blood, brain, liver, kidney
- Time and frequency of sampling: after 7 and 14 hours
- Method type(s) for identification: gas chromatography using the head-space sampling technique

Statistics:

The least squares method was used to find out the mathematical relationship of the inhaled and the blood n-pentanol concentrations. All results were statistically evaluated with variance analysis.

Details on absorption:

n-pentanol concentration in blood (y; nmol/g) was linearly correlated to the inhaled vapour concentration (x; ppm) at all times (table 1, y=0.05 x- 2.26, coefficient of correlation 0.90, N=30)

Details on distribution in tissues:

- The brain n-pentanol was related to the blood alcohol at 7 and 14 weeks although this relationship changed because the brain n-pentanol concentration decreased at 14 week s (table 1)
- The liver n-pentanol dehydrogenase activity did not change at all (table 2), but was slightly decreased in kidneys by the the two higher doses after 7 weeks, and control values were found after 14 weeks (table 3).

Metabolites identified:

yes

Details on metabolites:

Valeraldehyde (primary metabolite of the test substance) was found in the brain only at the highest dose level (600 ppm, table 1). Its concentration was roughly one third of the n-pentanol at 7 weeks, and it decreased more than n-pentanol at 14 weeks of exposure.

The microsomal cytochrome P-450 contents and 7-ethoxycoumarin O-deethylase activities in liver remained unaffected (table 2) while the kidney deethylase activity was enhanced in a dose-dependent manner at 7 weeks (table 3). This effect lessened after 14 weeks.

The brain acetylcholinesterase activity was above the control range by all doses at 7 wks (table 4). Similar effects were noted in the muscle specimens by the two higher doses at the same time. The increased activities were largely abolished after 14 weeks (table 4).

Table 1: Blood and brain n-pentanol concentrations

Exposure (ppm)	Exposure weeks
	7 (nmol/g wet weight)			14 (nmol/g wet weight)
	Blood	Brain		Blood	Brain
	n-pentanol	n-pentanol	Varaldehyde	n-pentanol	n-pentanol	Varaldehyde
100	2.9±0.7	2.2±0.3	0	4.7±3.0	2.8±1.8	0
300	13.0±6.0	16.1±7.5	0	11.6±4.2	6.4±1.4*	0
600	27.6±9.4	36.2±15.3	12.2±5.1	32.3±4.5	15.7±3.9*	1.6±0.5*
*: significantly different to 7 week values

Table 2: Effects of n-pentanol vapor exposure on rat liver mono-oxygenase and n-pentanol dehydrogenase activities

Exposure (ppm)	Exposure weeks
	7			14
	Cytochrome P-450 a	7-ECDE b	n-pentanol dehydrogenase c	Cytochrome P-450	7-ECDE	n-pentanol dehydrogenase
0	652±88	1.3±0.12	30±3.2	689±98	0.89±0.05	28±2.6
100	762±72	1.3±0.16	28±1.0	655±78	0.90±0.16	28±2.7
300	689±83	1.3±0.19	26±3.0	626±23	0.87±0.12	26±2.2
600	671±22	1.2±0.30	26±3.9	592±64	0.79±0.17	28±3.6
a pmol/mg microsomal protein; b7-Ethoxycoumarin O-deethylase, nmol/min x mg protein; c n-Pentanol dehydrogenase, nmol/min x mg cytosolic protein; each n=5

Table 3: Effects of n-pentanol vapor exposure on rat kidney mono-oxygenase and n-pentanol dehydrogenase artivities

Exposure (ppm)	Exposure weeks
	7			14
	Cytochrome P-450 a	7-ECDE b	n-pentanol dehydrogenase c	Cytochrome P-450	7-ECDE	n-pentanol dehydrogenase
0	206±31	20±2.6	6.2±0.66	172±24	7.0±0.11	5.8±1.7
100	220±17	23±0.0*	5.6±0.66	164±14	8.6±0.15	6.6±0.6
300	210±23	27±5.8*	5.0±0.48*	196±23	10.6±0.41	6.0±0.9
600	198±40	31±0.6*	5.0±0.80	186±13	12.1±0.27*	5.6±1.6
a pmol/mg microsomal protein;b7-Ethoxycoumarin O-deethylase, nmol/min x mg protein; cn-Pentanol dehydrogenase, nmol/min x mg cytosolic protein; each n=5; *different from control

Table 4: Effect of n-pentanol vapour on acetylcholinesterase activitv in brain and muscle

Exposure (ppm)	Exposure weeks
	7		14
	Brain	Muscle	Brain	Muscle
0	65±2	17±1.2	72±4	15±1.4
100	73±4**	18±0.6	79±9	15±1.2
300	73±5**	19±1.6*	82±2*	15±2.4
600	68±2*	19±0.6*	76±6	16±0.8
each n=5 rats; *different from control

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
Amyl Alcohol (1-pentyl alcohol) concentration in blood (y; nmol/g) was linearly correlated to the inhaled vapour concentration (x; ppm) at all times.
-The brain Amyl Alcohol (1-pentyl alcohol) was related to the blood alcohol at 7 and 14 weeks although this relationship changed because the brain Amyl Alcohol (1-pentyl alcohol) concentration decreased at 14 week s .
-The liver Amyl Alcohol (1-pentyl alcohol) dehydrogenase activity did not change at all, but was slightly decreased in kidneys by the the two higher doses after 7 weeks, and control values were found after 14 weeks.
Pentan-1-ol/Amyl alcohol is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, pentan-1-ol/Amyl alcohol need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Executive summary:

Amyl Alcohol (1-pentyl alcohol) concentration in blood (y; nmol/g) was linearly correlated to the inhaled vapour concentration (x; ppm) at all times.

-The brainAmyl Alcohol (1-pentyl alcohol)was related to the blood alcohol at 7 and 14 weeks although this relationship changed because the brainAmyl Alcohol (1-pentyl alcohol)concentration decreased at 14 week s .

-The liverAmyl Alcohol (1-pentyl alcohol)dehydrogenase activity did not change at all, butwas slightly decreased in kidneys by the the two higher doses after 7 weeks, and control values were found after 14 weeks.

Pentan-1-ol/Amyl alcohol is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore,pentan-1-ol/Amyl alcoholneed to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Reference 8

Endpoint:

basic toxicokinetics in vivo

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:

Objective of study:

metabolism

Qualifier:

no guideline available

Principles of method if other than guideline:

Metabolism study

GLP compliance:

Radiolabelling:

Species:

rabbit

Strain:

Chinchilla

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: ca. 3 kg
- Diet (e.g. ad libitum): a constant diet of 75 g rat cubes/day
- Acclimation period: at least 1 week

Route of administration:

oral: gavage

Vehicle:

water

Duration and frequency of treatment / exposure:

one application

Remarks:

Doses / Concentrations:
25 mmol

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine collected for 24 h

Metabolites identified:

yes

Details on metabolites:

After a single oral dose of 25 mmoles pentan-1-ol to rabbits, 6.7% of dose administered was excreted as glucuronides via urine. Glucuronide excretion occurred within 24 h.

After gavage administration of a dose of 25 mmol amyl alcohol/rabbit (corresponding to approx. 735 mg/kg bw) ca. 7%, 9%, and 10% of the dose was excreted by the rabbits into urine as glucuronides, when they had received pentan-1-ol, 3-methylbutan-1-ol, and 2-methylbutan-1-ol, respectively. The urine did not contain aldehydes or ketones.

Conclusions:

Interpretation of results : no bioaccumulation potential based on study results
After gavage administration of a dose of 25 mmol amyl alcohol/rabbit (corresponding to approx. 735 mg/kg bw) ca. 7%, 9%, and 10% of the dose was excreted by the rabbits into urine as glucuronides, when they had received pentan-1-ol, 3-methylbutan-1-ol, and 2-methylbutan-1-ol, respectively. The urine did not contain aldehydes or ketones.
Pentan-1-ol/Amyl alcohol is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, pentan-1-ol/Amyl alcohol need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Executive summary:

Reference 9

Endpoint:

dermal absorption in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

QSAR prediction:US EPA accepted QSAR method for chemicals properties assessment.

Qualifier:

no guideline required

Principles of method if other than guideline:

Using the DERMWIN v2.01 QSAR model

GLP compliance:

Remarks:

not applicable to QSAR models

Radiolabelling:

Species:

other: QSAR model,

Strain:

other: QSAR model,

Sex:

not specified

Type of coverage:

other: QSAR model

Vehicle:

other: QSAR model

Duration of exposure:

not applicable to QSAR models

Doses:

not applicable to QSAR models

No. of animals per group:

not applicable to QSAR models

Control animals:

Details on study design:

not applicable to QSAR models

Details on in vitro test system (if applicable):

not applicable to QSAR models

Signs and symptoms of toxicity:

not specified

Dermal irritation:

not specified

Absorption in different matrices:

A QSAR model predicts that the permeability of S-allyl O-pentyl dithiocarbonate to human skin is quite low. The permeability coefficient was determined to be 0.00279 mg/cm2, which is around 1% of the skin penetration rate.
Predicted dermally absorbed coefficient was determined to be Kp (est)=0.0182 cm/hr.

Predicted dermally absorbed coefficient was determined to be Kp (est)=0.0182 cm/hr.

Conclusions:

Executive summary:

Predicted dermally absorbed coefficient was determined to be Kp (est)=0.0182 cm/hr.

Reference 10

Endpoint:: dermal absorption in vivo
Type of information:: other: published data
Adequacy of study:: supporting 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:: Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2
Qualifier:: according to guideline
Guideline:: OECD Guideline 427 (Skin Absorption: In Vivo Method)
Deviations:: yes
Remarks:: Recovery was not in the required range. Volatile 14C-compounds were not collected.
GLP compliance:: no
Radiolabelling:: yes
Remarks:: (14C)-Ziram
Species:: rat
Strain:: Sprague-Dawley
Sex:: male
Details on test animals or test system and environmental conditions:: - Source: Charles River Laboratories, Wilmington, Massachusetts, US
- Weight: 237-267 g (Individual data of control group not reported)
Type of coverage:: open
Vehicle:: water
Duration of exposure:: 0.5, 1, 2, 4, 10 and 24 h
Doses:: 1.2, 9.9, 57.1% (w/v)
No. of animals per group:: 4 per timepoint
Control animals:: yes
Signs and symptoms of toxicity:: no effects
Dermal irritation:: not examined
Absorption in different matrices:: see Table 6_2-1
Total recovery:: see Table 6_2-1
Dose:: 0.086 mg/cm²
Parameter:: percentage
Absorption:: 28.5 %
Remarks on result:: other: 24 h
Dose:: 0.95 mg/cm²
Parameter:: percentage
Absorption:: 30.7 %
Remarks on result:: other: 24 h
Dose:: 7.25 mg/cm²
Parameter:: percentage
Absorption:: 4.89 %
Remarks on result:: other: 24 h
Conclusions:: Dithiocarbamates are related compounds to xanthates and xanthate esters. This is organosulfur compound is obtained by treating carbon disulfide with amine in the presence of sodium or potassium hydroxide: They arise from the reaction of the amine with CS2
Less than 0.3% of the administered radiolabel was retained in the carcass and was eliminated in the excreta within 24 h after exposure.
The mean amount absorbed (sum of radiolabel in urine, carcass, and skin at the test site) by 24 h was 29% of the administered dose in animals at 1.1 mg, 31% in those at 12 mg, and 5% for those at 91 mg, indicating non-linear dermal absorption.
Executive summary:: Less than 0.3% of the administered radiolabel was retained in the carcass and was eliminated in the excreta within 24 h after exposure. The mean amount absorbed (sum of radiolabel in urine, carcass, and skin at the test site) by 24 h was 29% of the administered dose in animals at 1.1 mg, 31% in those at 12 mg, and 5% for those at 91 mg, indicating non-linear dermal absorption.

Description of key information

S-allyl O-pentyl dithiocarbonate has not bioaccumulation potential. Xanthates and xanthate estersare metabolised in humans and animals to Carbon disulphide. Animal data for Xanthatesand xanthate esters indicate that up to 7% of dose may be eliminated as CS2 in breath. The kinetics of absorption, distribution and elimination of CS2 is by the excretion of the "biomonitoring metabolite TTCA" in the urine. Uptake in the blood is rapid and a blood equilibrium was reached in about 90 min, although a slight increase continued thereafter. Elimination was also rapid and biphasic (rapid and more slow phase). Terminal elimination times varied from 41 to 77 min.

Key value for chemical safety assessment

Bioaccumulation potential:: no bioaccumulation potential
Absorption rate - dermal (%):: 1

Additional information

It is known thatXanthatesand xanthate estersis metabolised to CS2 due to the presence of the CS2/cysteine (glutathione) conjugation product, 2-thiothiazolidine-4-carboxylic acid (TTCA)

The kinetics of absorption, distribution and elimination of CS2 is by the excretion of the "biomonitoring metabolite TTCA" in the urine. Uptake in the blood is rapid and a blood equilibrium was reached in about 90 min, although a slight increase continued thereafter. Elimination was also rapid and biphasic (rapid and more slow phase). Terminal elimination times varied from 41 to 77 min.

Carbon disulphide is both a reagent in the manufacture, as well as a decomposition product of xanthates. Carbon disulphide (CAS number 75–15–0) is both reagents used in the manufacture of S-allyl O-pentyl dithiocarbonate. Therefore, Carbon disulphide (CAS number 75–15–0) need to be considered in the assessment of S-allyl O-pentyl dithiocarbonate.

Toxicokinetics, metabolism and distribution

It is generally considered that adverse effects from exposure to xanthates (inhumans and animals) are associated with CS2 toxicity. It is not known what contribution to human toxicity is likely from inhalation/dermal absorption of CS2per se, as a xanthate decomposition product, and CS2 as a xanthate metabolite.

If metabolism to CS2 is associated with critical effects, then the limited dataavailable on xanthate metabolism indicates that similar toxicological profiles might be expected for animals and humans.

Animal and human studies indicate that the nervous system is the critical targetorgan for CS2 from inhalation exposure.

Xanthates are metabolised in humans and animals to CS2. Animal data forXanthatesand xanthate estersindicate that up to 7% of dose may be eliminated as CS2 in breath. The elimination vs time curves for potassium amyl xanthate in humans and guinea pigs indicate that biotransformation to CS2 is not saturated at doses studied (250 mg or 3.5 mg/kg in humans).

It is known that Xanthates and xanthate esters is metabolised to CS2 due to the presenceof the CS2/cysteine (glutathione) conjugation product, 2-thiothiazolidine-4-carboxylic acid (TTCA) in urine of exposed workers.

A single metabolism study (in French) published by Merlevede and Peters (1965) was identified in the above literature search. In this study, humans and guinea pigs were dosed with various xanthate compounds and the amount of expired CS2 monitored.

Following sub-cutaneous injection (70-200 mg/kg) of potassium ethyl xanthate in guinea pigs, up to 7% of the dose was expired as CS2 after 8 h, with maximum elimination between 1 - 2 h in most animals. The rate of elimination was doserelated,however the total percentage recovered was independent of dose. A morerapid rate of elimination was seen following sub-cutaneous injection (50 and 100mg/kg) of sodium ethyl xanthate, with CS2 expiration complete after 6 h, withmaximum elimination at 1 h (total recovery of CS2 was not reported).

Following oral intake in human volunteers, of 150 and 250 mg sodium ethyl xanthate, a maximum rate (13 – 57 μg/m3/h) of CS2 elimination in breath wasseen between 1-2 h, with complete elimination by 6 h (total recovery of CS2 wasnot reported).

The effect of alcohol on xanthate metabolism was also studied. In guinea pigs,concomitant sub-cutaneous injection of sodium diethyl xanthate and alcoholresulted in an increased rate of elimination, together with a greater total recoveryof CS2. These increases were directly related to the dose of alcohol.

An increased rate of elimination was also apparent in humans administered 250 mg sodium ethyl xanthate, following intake of 200 ml of alcohol (approximately18% by volume), however, the lack of a suitable control group preventedquantitative assessment.

The critical health effects from exposure to sodium ethyl xanthate in humans and animals are eye and skin irritation and possible neurological effects.

Acute effects, mainly gastrointestinal and CNS, were reported in one xanthateworker which were associated with possible inhalation and dermal exposure.

Retrospective monitoring indicated that exposure to CS2 levels may have been in excess of 60 ppm (187 mg/m3).

In 30 day inhalation (aerosol) studies with potassium amyl xanthate hepatotoxic effects were seen in dogs and mice at 23 mg/m3 (7.5ppm), and nephrotoxic effects in rats at 252 mg/m3 (81.5 ppm).

If metabolism to CS2 is associated with critical effects, then the limited data available on xanthate metabolism indicates that similar toxicological profiles might be expected for animals and humans.

Animal and human studies indicate that the nervous system is the critical targetorgan for CS2 from inhalation exposure. Apparently only one chronic inhalation study has been carried out in animals for CS2 and there are no chronic animal orhuman data pertaining to neurological effects following dermal exposure(ATSDR 1996).

Notwithstanding the available epidemiological data, it has generally beenconsidered that chronic adverse effects in humans from inhalation exposure toCS2 are associated with levels in excess of 10 ppm2.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Table A6_2-2: Concentations of radioactivity in blood from male rats following a single dermal application of (¹⁴C)-ziram

Dose level	µg ziram/g
Dose level	0.5 h	1 h	2 h	4 h	10 h	24 h
1.07 mg	0.002	ND	ND	ND	0.002	0.006 .006
11.9 mg	ND	ND	ND	ND	ND	ND
90.6 mg	ND	ND	ND	ND	ND	ND
ND Not detectable

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S-allyl O-pentyl dithiocarbonate

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Description of key information

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