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Basic toxicokinetics

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Administrative data

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.

Data source

Reference
Reference Type:
publication
Title:
Carbon disulfide neurotoxicity in rats: II. Toxicokinetics
Author:
Moorman MP, Sills RC, Collins BJ, and Morgan DL
Year:
1998
Bibliographic source:
NeuroToxicology, 19 (1): 89-88

Materials and methods

Objective of study:
toxicokinetics
Test guideline
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: compact and aerosol
Details on test material:
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.
Data taken from Sills et al. (1998a, Carbon disulfide neurotoxicity in rats: I. Introduction and study design. NeuroToxicology 19 (1): 83-88)
- Name of test material (as cited in study report): carbon disulfide (purchased from Aldrich Chemical Co., Milwaukee, WI);
- Molecular formula (if other than submission substance): CS2;
- Purity: > 99%.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals 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

Administration / exposure

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.
Doses / concentrations
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:
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:
no
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.

Results and discussion

Toxicokinetic / pharmacokinetic studies

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"

Metabolite characterisation studies

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.

Any other information on results incl. tables

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.

 

Applicant's summary and conclusion

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.