Carbon disulphide

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented and acceptable publication which is sufficient for assessement.

Data source

Reference

Reference Type:

publication

Title:

Toxicity to Carbon Disulfide in Developing Rats: LD50 Values and Effects on the Hepatic Mixed-Function Oxidase Enzyme System

Author:

Green E.C. and Hunter A.

Year:

1985

Bibliographic source:

Toxicology and Applied Pharmacology 78: 130-138

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The 24-h LD50 values of carbon disulfide (CS2) were estimated in 1-, 5-, 10-, 20-, 30-, and 40-day-old rats. Therefore, the "up-and-down" method of Brwonlee et al. (1953) was used. Furthermore, effects of CS2 on the liver were examined in developing rats after administration of 375 mg CS2/kg ip in corn oil (5 mL/kg). Plasma aspartate aminotransferase (AST) activity in rats 24 h following ip administration of CS2 was determined. Additionally, aniline hydroxylation (AH) and cytochrome P-450 concentrations in hepatic microsomes 24 h after ip administration of CS2 (375 mg/kg bw) was examined. Isolated microsomes from rats were incubated with 0.0002 M CS2 in the presence and absence of an NADPH-generating system and cytochrome P450 concentrations, AH, aminopyrine demethylation (AD) and benzo[a]pyrene hydroxylation were investigated.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Carbon disulphide

EC Number:

200-843-6

EC Name:

Carbon disulphide

Cas Number:

75-15-0

Molecular formula:

CS2

IUPAC Name:

methanedithione

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Animal Resources Center at East Carolina University School of Medicine
- Age at study initiation: Rats were used at 1, 5, 10, 20, 30, and 40 days of age.
- Housing: Until the rats were 30 days of age, newborn animals were caged with their mothers.
- Diet: ad libitum (Wayne Lab Blox (Chicago, III.))
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 0.5
- Humidity (%): 50 +/- 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

corn oil

Doses:

In vivo studies for determining the effect of CS2 on liver: 375 mg/kg bw.
In vitro studies: 0.0002 M CS2

No. of animals per sex per dose:

3 animals

Control animals:

yes

Statistics:

Two-way factorial analysis of variance, followed by a simple effects analysis. One-way analysis of variance followed by Duncan's new multiple range test. The level of signifcance for all statistical analysis was set at p < 0.05.

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

1 545 mg/kg bw

Based on:

test mat.

Remarks on result:

other: ip injected, 20-day-old rats

Effect levels 2

Sex:

male/female

Dose descriptor:

LD50

Effect level:

583 mg/kg bw

Based on:

test mat.

Remarks on result:

other: ip injected, 1-day-old rats

Mortality:

no details

Clinical signs:

not examined

Body weight:

not examined

Gross pathology:

not examined

Other findings:

- Other observations:
1) Plasma AST in 30- and 40-day old rats was significantly elevated above control values of plasma AST 24 h following a single dose of CS2. No significantly increase was observed in 1-, 5-, 10-, and 20-day-ols rats.
2) Twenty-four hours after administration of CS2 to 5-, 10-, 20-, 30-, and 40-day-old rats, cytochrome P-450 concentration and aniline hydroxylation (AH) were decreased significantly below control values, while cytochrome P-450 concentration and AH were not altered in 1-day-old rats.
3) After in vitro incubation of microsomes from rats of all ages examined with CS2 in the presence of an NADPH-generating system, both cytochrome P-450 and AH were significantly decreased below the corresponding control value in 5-, 10-, 20-, 30-, and 40-day-old rats. In vitro incubation of microsomes isolated from rats of the various ages studied with CS2 resulted in significant inhibition in comparison to the corresponding control of aminopyrine demethylation in 1-, 10-, 20-, 30-, and 40-day-old rats; benzo[a]pyrene hydroxylation was significantly decreased from control values in rats of all ages studied
4) When hepatic microsomes isolated from rats of all ages studied were incubated with C35S2, 35S was covalently bound to microsomal protein in the presence of an NADPH-generating system. Also, more 35S than 14C was covalently bound to microsomal membranes after incubation of microsomes isolated from rats of all ages studied with C35S2 or 14CS2 in the presence of an NADPH-generating system.

Applicant's summary and conclusion

Executive summary:

Acute toxicity and effects on hepatic mixed-function oxidase enzyme system of carbon disulfide was investigated in developing rats. The 24-hr LD50 values of carbon disulfide (CS2) were estimated in 1-, 5-, 10-, 20-, 30-, and 40-day-old rats. CS2 was least toxic to 20-day-old rats (LD50 1545 mg/kg, ip) and most toxic to 1-day-old rats (LD50 583 mg/kg, ip). Twenty-four hours after administration of CS2 (375 mg/kg, ip) to 1-, 5-, 10-, 20-, 30-, and 40-day-old rats, significant inhibition of cytochrome P-450 and aniline hydroxylation was observed in rats of all ages studied except the 1-day-old rats. Following incubation of hepatic microsomes isolated from 1-, 5-, 10-, 20-, 30-, and 40-day-old rats with CS2, decreases in activity of the hepatic mixed-function oxidase enzyme system and/or concentration of cytochrome P-450 were observed when an NADPH-generating system was present during incubation. When hepatic microsomes isolated from rats of all ages studied were incubated with C³⁵S2, ³⁵S was covalently bound to microsomal protein in the presence of an NADPH-generating system. Also, more ³⁵S than ¹⁴C was covalently bound to microsomal membranes after incubation of microsomes isolated from rats of all ages studied with C³⁵S2 or ¹⁴CS2 in the presence of an NADPH-generating system. The results of this research demonstrated the LD50 of CS2, the effects of CS2 on the hepatic mixed-function oxidase enzyme system, and that the conversion of CS2 to a covalently binding sulfer-containing biotransformation product varied with age in developing rats.